Annual/Termination Reports:

[12/20/2012] [08/02/2016] [12/29/2014] [12/10/2015] [12/06/2016]

Report Information

Participants

"Benninghoff, Abby, Abby.Benninghoff@usu.edu (attended on behalf of Roger Coulombe) (Utah State University);
"Bjeldanes, Len, lfb@nature.berkeley.edu (University of California, Berkeley);
"Harrington, Mike, wdal@lamar.colostate.edu (Colorado State University);
"Helferich, Bill, helferic@illinois.edu (University of Illinois);
"Lupis, Sarah (Colorado State University);
"Nerurkar, Pratibha, pratibha@hawaii.edu (University of Hawaii);
"Pestka, Jim, pestka@msu.edu (Michigan State University);
"Ricketts, Marie-Louise (University of Nevada Reno);
"Riley, Ron, rriley@saa.ars.usda.gov (USDA-ARS Athens, GA);
"Romagnolo, Donato (University of Arizona);
"Thavarajah, Pushparajah (North Dakota State University);
"Turner, Nancy (Texas A&M University);
"Weir, Tiffany, Tiffany.Weir@ColoState.edu (Colorado State University);
"Williams, David, david.williams@oregonstate.edu (Oregon State University);

Brief Summary of Minutes

Accomplishments

OBJECTIVE 1. Determine the mechanisms by which dietary bioactive compounds protect against human diseases. <br /> <br /> A focus of Oregon State University (OSU) researchers continues to be on dietary chemoprevention of cancer, specifically protection of the fetus/infant from transplacental carcinogens by dietary supplementation with plant phytochemicals or the whole foods from which they were derived. The emphasis continues to be on phytochemicals from cruciferous vegetables such as indole-3-carbinol, 3,3-diindolylmethane and sulforaphane. Mechanistic studies indicate that these phytochemical supplements may protect against cancer at least, in part, through epigenetic mechanisms.<br /> <br /> Researchers at Texas A&M University seek to understand how the intestinal environment (colon and bacteria) is modified in response to biologically active compounds present in the diet, with the end goal being the identification of compounds that are able to suppress inflammation and colon cancer. Ongoing studies include 1) determination of how byproducts of microbial fermentation, butyrate, affects epigenetic mechanisms of gene transcription, and 2) investigation of how polyphenolic molecules in sorghum affect the metabolism of microbiota protection against intestinal disease. <br /> <br /> Colorado State University (CSU), scientists have conducted dietary intervention studies to determine if the benefits of rice bran or dry bean in a colon cancer survivor cohort. After four weeks consumption of dry bean, healthy individuals and colon cancer survivors significantly reduced their total daily caloric intake, increased fiber intake, and had lower total cholesterol. In related work, a diet containing 10% rice bran fed to mice resulted in higher levels of fecal Lactobacillus and, when challenged with Salmonella infection, these animals showed lower Salmonella colonization and sustained pre-infection levels of fecal bacterial diversity and total Lactobacillus. CSU scientists are also studying Fuzhuan tea, a fermented Chinese tea from Hunan Province that is chemically distinct from green teas and shows a high level of phytochemical consistency across different lots and types of preparation (loose leaf, brick, coin, powder extract). Feeding Fuzhuan tea to laying hens resulted in lower egg cholesterol levels and increased feed efficiency and productivity. It showed anti-microbial activity against several enteric pathogens in vitro but was not as effective as green tea. <br /> <br /> Utah State University (USU) researchers are studying protective hepatic glutathione S-transferases (GST), universal phase II enzymes that detoxify dietary and environmental toxins and carcinogens such as aflatoxin B1 (AFB1) in an avian susceptibility model. Modern domestic turkeys, which are perhaps the most AFB1-sensitive animals known, lack GSTs with affinity toward the carcinogenic intermediate exo-aflatoxin B1-8-9-epoxide (AFBO). Recent research focused on the mechanism for this marked difference in response between these closely related breeds. Hepatic alpha-class GSTs (GSTAs) from wild turkeys, which are relatively AFB1- resistant, and those from heritage (hybrids developed in the early 20th century representing a genetic midpoint between wild and modern domestic turkeys), have the ability to detoxify AFBO, whereas those from domestic turkeys do not. These results suggest that hepatic GSTs in domestic turkeys are downregulated, silenced, or otherwise modified by one or more mechanisms. As in isolated populations of people with cancer susceptibility due to GST polymorphisms, loss of protective GST alleles in domestic turkeys is the likely mechanism for their extreme sensitivity compared to wild and heritage birds, fulfilling predictions that genetic improvement, domestication, and industry consolidation of commercial poultry result in the loss of genetic diversity, species fitness, and often, enhanced susceptibility to pathogens and environmental agents. In USU scientists have also functionally characterized three hepatic mu-class turkey GSTs (two from domestic turkey, and one from wild turkey) with emphasis on the detoxification of AFBO. The results suggested that although mu-class GSTs likely contribute to detoxification of xenobiotics, AFBO specific activity of the liver enzymes is more likely to be carried out by alpha class GSTs in turkeys.<br /> <br /> In other work, USU researchers have developed and are now testing a new rodent diet that models typical Western nutrition. Rodent cancer studies typically use defined diets with nutrient profiles optimized for rodent health. However, a defined rodent diet that represents typical American nutrition in all aspects, including calorie sources and macro- and micronutrient composition, was not available. Thus, a nutrient density approach to formulate the new Total Western Diet (TWD) based on NHANES data for macro- and micronutrient intakes. The TWD has fewer calories from protein and carbohydrate sources and twice that from fat as compared to the AIN-93 diet. The new diet contains more saturated and monounsaturated fats, less polyunsaturated fat, more complex carbohydrates and twice the level of simple sugars. The TWD includes less calcium, copper, folate, thiamine and vitamins B6, B12, D and E, but much more sodium. Since this newly devised diet that better represents typical American nutrition, it will be highly useful for studies employing animal models of human disease, including cancer. As proof of principle, the azoxymethane model of colorectal cancer was employed in mice fed either TWD or AIN93G basal diets supplemented with or without 0.2% green tea extract in the drinking water. Green tea extract reduced body fat percentage in both the TWD and AIN93G groups and decreased fasting glucose levels in mice fed TWD but not AIN93G. Mice fed TWD without green tea had more aberrant crypt foci (ACF) and a higher total crypt cell count compared to cohorts fed the AIN93G diet. Interestingly, green tea extract decreased ACF and total crypt cells in the TWD group but not in mice fed AIN93G. These results suggest that the Western dietary pattern promotes carcinogenesis and that supplementation with chemopreventive bioactives, such as green tea, might be beneficial to populations consuming a poor diet. <br /> <br /> Certain bioactive food components, including indole-3-carbinol (I3C) and 3,3-diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. Previously, we showed that dietary I3C is an effective transplacental chemopreventive agent in a dibenzo[def,p]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. The primary objective of the present study was to extend our chemoprevention studies in mice to an analogous human neoplasm in cell culture. Therefore, we tested the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells. Treatment of the T-ALL cell lines CCRF-CEM, CCRF-HSB2, SUP-T1 and Jurkat with DIM in vitro significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C. DIM (7.5 ¼M) arrested CEM and HSB2 cells at the G1 phase of the cell cycle and 15 ¼M DIM significantly increased the percentage of apoptotic cells in all T-ALL lines. In CEM cells, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis (BCL2L10, CD40LG, HRK, TNF, TNFRSF1A, TNFRSF25, TNFSF8, TRAF4). Similar anticancer effects of DIM were observed in vivo. Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice. These results suggest that there is a potential therapeutic application of DIM in T-ALL.<br /> <br /> University of Hawaii (UH) scientists are studying Native Hawaiian and Pacific Islander (NHPI) populations which have more than twice the rate of obesity-associated type 2 diabetes (T2D) as compared to Caucasians and more than five times as likely to die from T2D. Current therapies for obesity are complicated due to factors including an inability to maintain long-term weight loss and drug-drug interactions. In addition, conventional therapies may not be affordable, suitable and/or acceptable for culturally sensitive minority populations. Eliminating health disparities among ethnic minorities is one of the three goals of Healthy People 2010 initiative. There is a growing awareness and mounting body of scientific evidence, that successful implementation of strategies to control T2D among ethnic minorities will require culturally appropriate interventions. UH researchers have demonstrated that bitter melon juice (BMJ) improves not only glucose and lipid metabolism, but also prevent weight gain in mice fed high-fat-diet (HFD) containing 58% fat. Mechanistic studies indicate a role for chronic inflammation in pathophysiology of obesity and T2D. Current studies are planned to understand how BMJ influences gut microbiota and inflammation. In other work, UH has recently demonstrated that bitter melon juice (BMJ) improves not only glucose and lipid metabolism, but also prevent weight gain in mice fed high-fat-diet (HFD) containing 58% fat. Studies further suggest that BMJ decreases macrophage infiltration and inflammation in adipose tissue of mice fed HFD. <br /> <br /> <br /> OBJECTIVE 2. Elucidate mechanisms of action of dietary toxicants and develop biomarkers for human risk assessment and disease prevention. <br /> <br /> Michigan State University (MSU) researchers tested the hypothesis that deoxynivalenol (DON), a trichothecene mycotoxin known to commonly contaminate grain-based foods, induces the release of satiety hormones and that this response corresponds to the toxins anorectic action. Acute intraperitoneal (ip) and oral ingual exposure to DON had no effect on plasma glucagon-like peptide-1, leptin, amylin, pancreatic polypeptide, gastric inhibitory peptide or ghrelin, however, the toxin was found to robustly elevate peptide YY (PYY) and cholecystokinin (CCK) which peaked within 15 to 240 min, corresponding with depressed rates of food intake. Direct administration of exogenous PYY or CCK similarly caused reduced food intake. Food intake experiments using the NPY2 receptor antagonist BIIE0246 and the CCK1A receptor antagonist devazepide, individually, suggested that PYY mediated DON-induced anorexia but CCK did not. Oralingual exposure to DON induced plasma PYY and CCK elevation as well as anorexia comparable to that observed for ip exposure. Taken together, these findings suggest that PYY might be one critical mediator of DON-induced anorexia and, ultimately, growth suppression.<br /> <br /> USDA researchers at the U. Georgia (USDA-GA) in collaboration with Guatemalan scientists through the Centro de Investigaciones en Nutricion y Salud in Guatemala (CIENSA) are relating biomarkers for fumonisin exposure (urinary fumonisin B1) and to effects (changes in sphingoid base 1-phosphates in blood spots). Approximately 1,200 urine and blood spot samples have been collected and analyzed from three locations in rural Guatemala. Maize samples (n=90) from the same locations have been collected and analyzed. The results show that fumonisin B1 in urine is correlated with the level of fumonisin in the maize collected from each locality and that urinary fumonisin B1 is significantly correlated with evidence indicating elevated levels of sphingoid base 1-phosphates in blood spots. Because the results of the first year of the study have demonstrated strong evidence for linking fumonisin exposure to disruption of sphingolipid metabolism in humans, a request was made to the NIH National Institute of Child Health & Human Development to modify the study design so as to identify two new sampling locations (one high exposure and one low exposure) to be used to validate the findings thus far. This request was approved. A survey of fumonisin contamination in maize across Guatemala is currently in progress (> 400 samples thus far) and once completed the Human Subjects Protocols will be modified and resubmitted to both the MOH and the Institute of Nutrition of Central America and Panama (an NIH approved IRB) for approval.<br /> <br /> OSU researchers have elucidated novel mechanisms of action and biomarkers associated with food-borne carcinogens (polycyclic aromatic hydrocarbons, cooked meat mutagens) or other known or potential compounds such as nanomaterials, pesticides and perfluoroalkyl acids. These have included molecular biomarkers such as alterations in levels of tumor suppressor genes and DNA adducts in addition to biological endpoints.<br /> University of Arizona (UA) researchers are studying how epigenetic mechanisms contribute to reduced expression of the tumor suppressor gene BRCA-1 in sporadic breast cancers. Through environmental exposure and diet, humans are exposed to xenobiotics and food compounds that bind the aromatic hydrocarbon receptor (AhR). AhR-ligands include the dioxin-like and tumor promoter 2,3,7,8 tetrachlorobenzo-p-dioxin (TCDD). The activated AhR regulates transcription through binding to xenobiotic response elements (XRE=GCGTG) and interactions with transcription cofactors. It was previously reported on the presence of several XRE in the proximal BRCA-1 promoter, and that the expression of endogenous AhR was required for silencing of BRCA-1 expression by TCDD. It was discovered that in estrogen receptor-± (ER-±)-positive and BRCA-1 wild-type MCF-7 breast cancer cells, the treatment with TCDD attenuated 17²-estradiol (E2)-dependent stimulation of BRCA-1 protein and induced hypermethylation of a CpG island spanning the BRCA-1 transcriptional start site of exon-1a. These and related observations provide mechanistic evidence for AhR-agonists in the establishment of BRCA-1 promoter hypermethylation and the basis for the development of prevention strategies based on AhR antagonists. UA researchers have also found that gestational activation of the AhR with TCDD induced CpG methylation of a BRCA-1 promoter region flanking an XRE, expression of CYP1A1 mRNA, and association of DNA methyltrasferase-1 with the BRCA-1 gene. The in utero treatement with TCDD reduced in offspring BRCA-1 protein expression and the number of lobular and alveolar mammary structures. These gestational effects of TCDD were antagonized by the cotreatment with resveratrol. In mammary tumors induced post-pubertally with DMBA, reduced BRCA-1 and estrogen receptor-a protein expression coincided with hypermethylation of the BRCA-1 promoter, and increased expression of AhR protein and CYP1B1 mRNA. Thus maternal and post-pubertal activation of the AhR may contribute to mammary carcinogenesis through epigenetic deregulation of BRCA-1 expression. <br /> <br /> <br /> OBJECTIVE 3. Discover and characterize novel bioactive dietary compounds that have beneficial or adverse effects on human health. <br /> <br /> MSU researchers compared the capacities of deoxynivalenol (DON) congeners 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), fusarenon X (FX) and nivalenol (NIV) to induce anorexia in the mouse. As previously observed for DON, anorectic responses to 3-ADON and 15-ADON in the B6C3F1 female mouse following both intraperitoneal (ip) and oral exposure were transient, lasting only a few hours, with food intake recovering to control levels within 16 h. Both resulted data and a prior DON study suggest that anorectic responses to 8-ketotrichothecenes were always greater when administered ip as compared to oral exposure and follow an approximate rank order of NIV>FX>DONH3-ADONH15-ADON for ip exposure and FX>NIV>DONH3-ADONH15-ADON for oral exposure. In other work MSU researchers compared potencies of DON congens in the mink emesis model following intraperitoneal (ip) and oral administration. All five congeners dose-dependently induced emesis by both administration methods. With increasing doses, there were marked decreases in latency to emesis with corresponding increases in emesis duration and number of emetic events. The effective doses resulting in emetic events in 50% of the animals (EDs50) for ip exposure to DON, 15-ADON, 3-ADON, FX and NIV were 80, 170, 180, 70, and 60 µg/kg bw respectively, and for oral exposure were 30, 40, 290, 30 and 250 µg/kg bw, respectively. The emetic potency of DON determined in mice was comparable to that reported in analogous studies conducted in pigs and dogs suggesting that the mink is a suitable small animal model for investigating acute trichothecene toxicity. The use of a mouse pica model, based on the consumption of kaolin, was also evaluated as a possible surrogate for studying emesis but was found unsuitable. From a public health perspective, comparative anorectic and emetic potency data derived from small animal models such as the mink should be useful for establishing toxic equivalency factors for DON and trichothecenes, and other emesis-inducing agents. <br /> <br /> University of California-Berkeley (UC-B) researchers are assessing potential of certain microbial and plant sources from Indonesia for anticancer, immune modulating and neurological activities and to provide in vitro bioassay support for discovery of the active components. To achieve these objectives they employ cell-based assays for cytotoxicity in cultured tumor cells, NF-?B activation or inhibition in cultured macrophages, and opioid G-protein coupled receptor (GPCR) activation or inhibition in cultured human kidney cells. Screening of a total of 382 extracts of microorganism isolates and 228 plant extracts was completed for their potential anticancer activity. Follow-up studies of active substances will be conducted in rodents. <br /> University of Nevada-Reno (UN-R) researchers are investigating the molecular actions of a grape seed procyanidin extract (GSPE) and how it lowers serum triglyceride (TG) levels. The potential link between the intestine and the liver in the TG-lowering ability of GSPE was investigated by conducting both in vitro and in vivo expts. Using a human colon cell line, namely Caco2 cells, which express the farnesoid x recepor (FXR) it was found that GSPE alters FXR-target gene expression in a manner that indicates that it may be a gene-selective bile acid receptor modulator. Current studies are underway to determine the effects that GSPE has in vivo in a mouse model on intestinal FXR-target genes and how this may impact enterohepatic bile acid circulation and the subsequent TG-lowering ability of this extract lower. <br /> <br /> <br /> OBJECTIVE 4. Increase beneficial or decrease adverse effects of bioactive constituents and microbes in food.<br /> <br /> UA researchers reviewed from epidemiological and preclinical studies addressing the potential benefits of diets based on flavonoids for cancer prevention. Flavonoids are subdivided into subclasses including flavonols, flavones, flavanones, flavan-3-ols, anthocyanidins, and isoflavones. Epidemiological studies suggest dietary intake of flavonoids may reduce the risk of tumors of the breast, colon, lung, prostate, and pancreas. However, some studies have reported inconclusive or even harmful associations. A major challenge in the interpretation of epidemiological studies is that most of the data originate from case-control studies and retrospective acquisition of flavonoid intake. Differences in agricultural, socio-demographics, and lifestyle factors contribute to the heterogeneity in the intake of flavonoids among populations residing in the U.S., Europe, and Asia. Dose and timing of exposure may influence the anticancer response to flavonoid-rich diets. A limited number of intervention trials of flavonoids have documented cancer preventative effects. Proposed anticancer mechanisms for flavonoids are inhibition of proliferation, inflammation, invasion, metastasis, and activation of apoptosis. Prospective studies with larger sample sizes are needed to develop biomarkers of flavonoid intake and effect. Mechanistic studies are needed to ascertain how flavonoid-rich diets influence gene regulation for cancer prevention.<br /> <br /> The role estradiol plays in estrogen receptor (ER) positive in breast cancer (BC) is well-documented, but the way it contributes to ER-negative BC remains unclear. University of Illinois (UI) researchers utilized an experimental model of BC metastasis into lung by injecting ER-negative murine 4T1 cells into mice via the lateral tail vein. A 56% metastasis occurrence rate following the injection of 5×103 cells was observed, thus this cell number was selected to study the potential stimulatory effect of estradiol on ER-negative BC metastasis. Female ovariectomized mice were randomized into estradiol and control groups with 16 mice per group, and estradiol pellets were implanted subcutaneously in the estradiol group. Results demonstrated that estradiol accelerated BC metastasis as indicated by bioluminescent imaging. In addition, estradiol enhanced metastatic tumor colony formation and increased the size of tumor nodules in the lungs, which were due, in part, to the increase in proliferative cells in the metastatic tumors. In vitro, estradiol increased the motility and invasion of 4T1 cells, and the stimulatory effect on cell motility was not blocked by ICI 182, 780, confirming that ER was not involved in the process. Results from the present study suggest that estradiol plays a role in ER-negative BC metastasis in the whole animal.<br /> University of North Dakota (UND) researchers have initiated studies to (1) isolate low digestible carbohydrates from corn distillers grain (DG) (2) prepare nanomaterials from the resistant starches isolated from corn DG (3) prepare corn DG protein and polysaccharides based coacervates (4) evaluate safety aspects using animal models prior to using for various food and pharmaceutical applications.<br /> <br /> USDA scientists at the Western Regional Research Center in California (USDA-CA) conducted studies on how natural products can be used to reduce the risk of foodborne pathogens, Oregano oil (0.5%) and green tea polyphenols (3%) reduced E. coli O157:H7 strains containing Shiga toxin Stx-1 and Stx-2 genes on lettuce and spinach to below detection limits. Lemongrass oil was highly effective in reducing the Salmonella enterica population on contaminated organic leafy greens. Apple, carrot, and hibiscus edible films containing carvacrol and cinnamaldehyde inactivated of Listeria monocytogenes on ham and bologna. Plant extracts, spices, and essential oils inactivate Escherichia coli O157:H7 and reduced formation of carcinogenic heterocyclic amines in cooked beef patties. A three-factor model can be used to estimate processing times and temperatures required to achieve a 7.0 log reduction of Salmonella in ground chicken. Less sodium chloride (which contributes to hypertension) is needed to reduce heat resistance of Listeria monocytogenes in ground beef with added apple polyphenols. Dietary rice hull liquid smoke (1%) and Hericium erinaceus mushroom extracts protected mice against Salmonella-induced mortality by stimulation of the immune system.<br /> <br /> Another effort of OSU researchers has been focused on reducing human health risks from food-borne pathogens and environmental contaminants. Indole-3-carbinol is especially potent in reducing the risk to the fetus from exposure in utero to chemical carcinogens ingested in food<br />

Publications

Andrade, J. E., Twaddle, N.C., Helferich, W.G. and Doerge, D.R., (2010). Absolute Bioavailability of Isoflavones from Soy Protein Isolate-Containing Food in Female Balb/c Mice. J Agric Food Chem;58:4529-36. <br /> <br /> Andrade, J.E., Ju, Y.H., Baker, C., Wei, X., Doerge, D.R. and W.G. Helferich, Long-term dietary exposure of genistein and soy protein isolate containing genistein affect the progression of human breast cancer (MCF-7) cells after genistein withdrawal in athymic mice. 2012. (Submitted).<br /> <br /> Aronchik I, Chen T, Durkin KA, Horwitz MS, Preobrazhenskaya MN, Bjeldanes LF, Firestone GL. Target protein interactions of indole-3-carbinol and the highly potent derivative 1-Benzyl-I3C with the C-terminal domain of human elastase uncouples cell cycle arrest from apoptotic signaling. Mol Carcinog. 2011 Oct 19. doi: 10.1002/mc.20857. <br /> <br /> Baldwin, T.T., Riley, R.T., Zitomer, N.C., Voss, K.A., Coulombe, R.A. Jr., Pestka, J.J., Williams, D.E. and Glenn, A.E. (2011) The Current State of Mycotoxin Biomarker Development in Humans and Animals and the Potential for Application to Plant Systems World Mycotoxin Forum J. 4:257-270.<br /> <br /> Barnett BA and Weir TL (2012) Bacterial secretion. In: Secretions and Exudates in Biological Systems (eds. Baluska F, Vivanco JM). Springer, Berlin, Germany.<br /> <br /> Beaver, L.M., Yu, T.-W., Sokolowski, E.I., Williams, D.E., Dashwood, R.H. and Ho, E. (2012). 3,3Diindolylmethane, but not Indole-3-Carbinol, Inhibits Histone Deacetylase Activity in Prostate Cancer Cells. Toxicol. Appl. Pharmcol. 263:345-351.<br /> <br /> Benninghoff, A.D., Orner, G.A., Buchner, C., Hendricks, J.D., Duffy, A.M. and Williams, D.E. (2012) Promotion of Hepatocarcinogenesis by Perfluoroalkyl Acids in Rainbow Trout. Toxicol. Sci. 125:60-78.<br /> <br /> Bondy, G.S., Mehta, R., Caldwell, D., Coady, L., Armstrong, C., Savard, M., Miller, J. D., Chomyshyn, E., Bronson, R., Zitomer, N.C., Riley, R.T. (2012) Effects of long term exposure to the mycotoxin fumonisin B1 in p53 heterozygous and p53 homozygous transgenic mice Food and Chemical Toxicology DOI 10.1016/j.fct.2012.07.024<br /> <br /> Borresen EC, Henderson AJ, Kumar A, Weir TL, Ryan EP (2012) Fermented foods: Patented approaches and formulations for nutritional supplementation and health promotion. Recent Patents on Food, Nutrition & Agriculture. 4, in press.<br /> <br /> Bulder, A. S., Arcella, D., Bolger, M., Carrington, C., Kpodo, K., Resnik, S., Riley, R.T., Wolterink, G., and Wu, F. (2012) Fumonisins (addendum), In: Safety evaluation of certain food additives and contaminants. Geneva, World Health Organization, WHO Food Additives Series, 65, 325-794.<br /> <br /> Caiozzi G, Wong BS, Ricketts ML (2012) Dietary modification of metabolic pathways via nuclear hormone receptors. Cell Biochem Funct. 30(7):531-51. doi: 10.1002/cbf.2842. Epub 2012 Jul 2.<br /> <br /> Callihan, P., Zitomer, N., Kennedy, P., Lynch, K.R., Riley, R.T. and Hooks, S.B. (2012) Distinct generation, pharmacology, and distribution of sphingosine 1-phosphate and dihydro-sphingosine 1-phosphate in human neural progenitor cells. Neuropharmacology 62, 988-996.<br /> <br /> Carey, S. A., Plopper, C. G., Hyde, D. M., Islam, Z., Pestka, J. J., and Harkema, J. R. (2012). Satratoxin-G from the black Mold Stachybotrys chartarum induces rhinitis and apoptosis of olfactory sensory neurons in the nasal airways of rhesus monkeys. Toxicol Pathol 40, 887-898.<br /> <br /> Cho, Y., H. Kim, et al. (2011). "A chemoprotective fish oil- and pectin-containing diet temporally alters gene expression profiles in exfoliated rat colonocytes throughout oncogenesis." J Nutr 141(6): 1029-1035.<br /> <br /> Cho, Y., N. D. Turner, et al. (2012). "A chemoprotective fish oil/pectin diet enhances apoptosis via Bcl-2 promoter methylation in rat azoxymethane-induced carcinomas." Experimental Biology & Medicine In press.<br /> <br /> Cimafranca, M.A., Davila, J., Ekman, G.C., Andrews, R.N., Neese, S.L., Peretz, J., Woodling, K.A., Helferich, W.G., Sarkar, J., Flaws, J.A., Schantz, S.L., Doerge, D.R., and Cooke, P.S. (2010). Acute and chronic effects of oral genistein administration in neonatal mice. Biol Reprod. 2010 83(1):114-21. <br /> <br /> Clarke, J.D., Hsu, A., Williams, D.E., Dashwood, R.H., Stevens, J.F., Thuillier, P, Shannon, J. and Ho, E. (2011) Metabolism and Tissue Distribution of Sulforaphane in Nrf2 Knockout and Wild-Type Mice. Pharmacol. Res. 28:3171-3179 NIHMSID #351443.<br /> <br /> Crowell, S.R., Amin, S.G., Anderson, K.A., Krishnegowda, G., Sharma, A.K., Soelberg, J.J, Williams, D.E. and Corley, R.A. (2011). Preliminary Physiologically Based Pharmacokinetic Models for Benzo[a]Pyrene and Dibenzo[def,p]Chrysene in Rodents. Toxicol. Appl. Pharmacol. 257:365-376.<br /> <br /> De Assis, S., Warri, A., Benitez, C., Helferich, W.G., and Hilakivi-Clarke, L.A., (2011). Protective effects of prepubertal genistein exposure on mammary tumorigenesis are dependent on BRCA1 expression. Cancer Prev Res. 4(9):1436-48. <br /> <br /> de Roos B, Romagnolo DF. Proteomic approaches to predict bioavailability of fatty acids and their influence on cancer and chronic disease prevention. J Nutr. 2012 Jul;142(7):1370S-6S. Epub 2012 May 30. Review.<br /> <br /> Du, M., Yang X., Hartman J.A., Cooke, P.S., Doerge D.R., Ju Y.H., Helferich, W.G. (2012). Low-dose dietary genistein negates the therapeutic effect of tamoxifen in athymic nude mice. Carcinogenesis. 33(4):895-901.<br /> <br /> Feduccia AA, Wang Y, Simms JA, Yi HY, Li R, Bjeldanes L, Ye C, Bartlett SE. Locomotor activation by theacrine, a purine alkaloid structurally similar to caffeine: involvement of adenosine and dopamine receptors. Pharmacol Biochem Behav. 2012:102(2):241-8. <br /> <br /> Flannery, B. M., Clark, E. S., and Pestka, J. J. (2012). Anorexia induction by the trichothecene deoxynivalenol (vomitoxin) is mediated by the release of the gut satiety hormone peptide YY (PYY). Toxicol Sci.<br /> Gelineau-van Waes, J., Rainey, M.A., Maddox, J. R., Voss, K. A., Sachs, A. J., Gardner, N. M., Wilberding, J. D. and Riley, R. T. (2012) Increased sphingoid base-1-phosphates and failure of neural tube closure after exposure to fumonisin or FTY720. Birth Defects Research Part A: Clinical and Molecular Teratology 2012 Sep 18. DOI: 10.1002/bdra.23074. [Epub ahead of print]<br /> <br /> George, N. I., J. R. Lupton, et al. (2010). "Evaluation of fecal mRNA reproducibility via a marginal transformed mixture modeling approach." BMC Bioinformatics 11: 13.<br /> <br /> He, K., Pan, X., Zhou, H. R., and Pestka, J. (2012a). Modulation of inflammatory gene expression by the ribotoxin deoxynivalenol involves coordinate regulation of the transcriptome and translatome. Toxicol Sci.<br /> <br /> He, K., Zhou, H. R., and Pestka, J. J. (2012b). Mechanisms for ribotoxin-induced ribosomal RNA cleavage. Toxicol Appl Pharmacol. 265, 10-18<br /> <br /> He, K., Zhou, H. R., and Pestka, J. J. (2012c). Targets and intracellular signaling mechanisms for deoxynivalenol-induced ribosomal RNA cleavage. Toxicol Sci 127, 382-390.<br /> <br /> Hilakivi-Clarke, L. Andrade, J.E., and Helferich. W.G. (2010). Is Soy Consumption good or bad for the breast? J. Nutr. 140(12):2326S-34S. <br /> <br /> Hintze, K.J., Benninghoff, A.D. and Ward, R.E. (2012) Formulation of the Total Western Diet (TWD) as a basal diet for rodent cancer studies. Journal of Agricultural and Food Chemistry 60 (27): 6736-6742.<br /> <br /> Ho, E., Beaver, L.M., Williams, D.E. and Dashwood, R.H. (2011) Dietary factors and epigenetic regulation for prostate cancer. Adv. Nutr. 2:497-510.<br /> <br /> Hsu, A., Bray, T.M., Helferich, W.G., Doerge, D.R., and Ho, E., (2010). Differential effects of whole soy extract and soy isoflavones on apoptosis in prostate cancer cells. Exp. Biol. Med. 2010;235:90-7. <br /> <br /> Hsu, A., Wong, C.P., Williams, D.E., Dashwood, R.H. and Ho, E. (2011). Promoter De-Methylation of Cyclin D2 by Sulforaphane in Prostate Cancer Cells. Clin. Epigenetics 3:3-<br /> <br /> Jackson, L.S., Jablonski, J.J, Bullerman, L.B., Bianchini, A., Hanna, M.A., Voss, K.A., Hollub, A.D., Ryu D. (2011) Reduction of fumonisin B1 in corn grits by twin-screw extrusion. Journal of Food Science 76, T150-155.<br /> <br /> Jeffery, J. L., N. D. Turner, et al. (2012). "Carotenoid bioaccessibility from nine raw carotenoid-storing fruits and vegetables using an in vitro model." J Sci Food Agric 92(13): 2603-2610.<br /> <br /> Johnson TA, Sohn J, Inman WD, Estee SA, Loveridge ST, Vervoort HC, Tenney K, Liu J, Ang KK, Ratnam J, Bray WM, Gassner NC, Shen YY, Lokey RS, McKerrow JH, Boundy-Mills K, Nukanto A, Kanti A, Julistiono H, Kardono LB, Bjeldanes LF, Crews P. Natural product libraries to accelerate the high-throughput discovery of therapeutic leads. J Nat Prod. 2011;74(12):2545-55. <br /> Johnson TA, Sohn J, Vaske YM, White KN, Cohen TL, Vervoort HC, Tenney K, Valeriote FA, Bjeldanes LF, Crews P. Myxobacteria versus sponge-derived alkaloids: the bengamide family identified as potent immune modulating agents by scrutiny of LC-MS/ELSD libraries. Bioorg Med Chem. 2012 Jul 15;20(14):4348-55. <br /> <br /> Keller AC, Weir TL, Broeckling CD, Ryan EP (2012) Antibacterial activity and phytochemical profile of fermented Camellia sinensis (Fuzhuan tea). Food Research International. Under revision<br /> <br /> Kim, J.E., Bunderson, B., Croasdell, A., and R.A. Coulombe, Jr. (2011) Functional Characterization of Alpha-class Glutathione S-transferases from the Turkey (Meleagris gallopavo) Toxicological Sciences doi: 10.1093/toxsci/kfr212<br /> <br /> Kim, J.E., Bunderson, B., Croasdell, A., Reed, K.M, and R.A. Coulombe, Jr. (20XX) Alpha-class glutathione S-transferases in wild turkeys: Characterization and Role in Resistance to the Carcinogenic Mycotoxin AflatoxinB1. PLoS One (submitted for publication).<br /> <br /> Kumar A, Henderson A, Forster GM, Chen MH, Goodyear AW, Bauer JE, Weir TL, Leach JE, Dow SW, Ryan EP (2012) Dietary Rice Bran Promotes Resistance to Salmonella Colonization and Mucosal Invasion in Mice. BMC Microbiology. 12, 71.<br /> <br /> Kumar M, Roe K, Nerurkar PV, Namekar M, Orillo B, Verma S, Nerurkar VR. Impaired virus clearance, compromised immune response and increased mortality in type 2 diabetic mice infected with West Nile virus. PLoS One. 2012;7(8):e44682. doi: 10.1371/journal.pone.0044682. Epub 2012 Aug 31<br /> <br /> Lemlioglu-Austin, D., N. D. Turner, et al. (2012). "Effects of sorghum [Sorghum bicolor (L.) Moench] crude extracts on starch digestibility, estimated glycemic index (EGI), and resistant starch (RS) contents of porridges." Molecules 17(9): 11124-11138.<br /> <br /> Lemlioglu-Austin, D., N. D. Turner, et al. (2012.). "Effects of brans from specialty sorghum varieties on in vitro digestibility of soft and hard sorghum endosperm porridges." Cereal Chemistry 89: 190-197.<br /> <br /> Leonardi, T., J. Vanamala, et al. (2010). "Apigenin and naringenin suppress colon carcinogenesis through the aberrant crypt stage in azoxymethane-treated rats." Exp Biol Med (Maywood) 235(6): 710-717.<br /> <br /> McQuistan, T.J, Simonich, M.T., Pratt, M.M., Pereira, C.B, Hendricks, J.D., Dashwood, R.H., Williams, D.E. and Bailey, G.S. (2011) Cancer Chemoprevention by Dietary Chlorophylls: A 12,000-Animal Dose-Dose Matrix Biomarker and Tumor Study. Fd. Chem. Toxicol. Nov. 3 [Epub ahead of print].<br /> <br /> Myung, K., Zitomer, N., Duvall, M., Glenn, A.H., Riley R.T. and Calvo A.M. (2012) The conserved global regulator VeA is necessary for maize seedling disease in Fusarium verticillioides Plant-Pathology 61, 152-160. 2012.<br /> <br /> Neese, S.L., Bandara,S.B., Doerge, D.R., Helferich, W.G., Korol, D.L., Schantz, S.L. (2011). Effects of multiple daily genestein treatment on executive function in middle-aged rats. Neurotoxicology & Teratology. 34(1):187-95.<br /> Neese, S.L., Wang, V.C., Doerge, D.R., Woodling, K.A., Andrade, J.E., Helferich, W.G., Korol, D.L., and Schantz, S.L., (2010). Impact of dietary genistein and aging on executive function in rats. Neurotoxicol Teratol. 32(2): p. 200-211. <br /> <br /> Nerurkar PV, Nishioka A, Eck PO, Johns LM, Volper E, Nerurkar VR. Regulation of glucose metabolism via hepatic forkhead transcription factor 1 (FoxO1) by Morinda citrifolia (noni) in high-fat diet-induced obese mice. Br J Nutr. 2012 Jul;108(2):218-28.<br /> <br /> Papoutsis AJ, Borg JL, Selmin OI, Romagnolo DF. BRCA-1 promoter hypermethylation and silencing induced by the aromatic hydrocarbon receptor-ligand TCDD are prevented by resveratrol in MCF-7 cells. J Nutr Biochem. 2012 Oct;23(10):1324-32. doi: 10.1016/j.jnutbio.2011.08.001. Epub 2011 Dec 23. <br /> <br /> Parasramka, M., Ho, E., Williams, D.E. and Dashwood, R.H. (2011). MicroRNAs, Diet and Cancer Chemoprevention: New Mechanistic Insights on the Epigenetic Action of Phytochemicals. Molec. Carcinogenesis 51:213-230.<br /> <br /> Parasramka, M.A., Dashwood, W.M., Wang, R., Abdelli, A., Bailey, G.S., Williams, D.E., Ho, E. and Dashwood, R.H. (2012) Let-7/c-Myc/Lin28 Axis in 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-Induced Rat Colon Tumors and the Influence of Dietary Spinach. Molec. Nutr. Fd. Res., in press.<br /> <br /> Petrovi, D.; Sivapragasam, N.; Thavarajah, D.; Gelling, V.; Thavarajah, P. Resistant starch nanoparticles for potential colonic drug and nutrient delivery. Biomacromolecules (in preparation)<br /> <br /> Petrovi, D.; Sivapragasam, N.; Thavarajah, D.; Gelling, V.; Thavarajah, P. (2013). Corn resistant starch nanoparticles as encapsulation material for micronutrient and pharmaceutical drug delivery. ACS National Meeting oral presentation (Abstract #12061); presenting author<br /> <br /> Rajendran, P., Ho, E., Williams, D.E. and Dashwood, R.H. (2011) Dietary Phytochemicals, HDAC Inhibition and DNA Damage/Repair Defects in Cancer Cells. Clin. Epigenetics 3:4- NIHMS #346513.<br /> <br /> Rajendran, P., Kidane, A.I., Yu, T.-W., Dashwood, W.-M., Löhr, C.V., Ho, E., Williams, D.E. and Dashwood, R.H. (201x) HDAC Turnover, CtIP Acetylation and Dysregulated DNA Damage in Colon Cancer Cells Treated With Sulforaphane and Related Dietary Isothiocyanates. Carcinogenesis, in press.<br /> <br /> Rajendran, Praveen, DeLage, B., Dashwood, W.M., Yu, T.-W., Wuth, B., Williams, D.E., Ho, E. and Dashwood, R.D. (2011) Histone Deacetylase Turnover and Recovery in Sulforaphane-Treated Colon Cancer Cells: Competing Actions of 14-3-3 and Pin1 in HDAC3/SMRT Corepressor Complex Dissociation/Reassembly. Molec. Cancer 10:68 doi:10.1186/1476-4598-10-68.<br /> <br /> Rawal, S., and R.A. Coulombe, Jr. (2011). Metabolism of Aflatoxin B1 in Turkey Liver Microsomes: The Relative Roles of Cytochromes P450 A15 and 3A37. Toxicology and Applied Pharmacology 254:349-354. doi:10.1016/j.taap.2011.05.010<br /> <br /> Riley , R.T., Torres, O.,,Showker, J.L., Zitomer, N.C., Matute, J., Voss, K.A., Gelineau-van Waes, J., Maddox, J.R., Gregory, S.G., Ashley-Koch, A.E. (2012) The Kinetics of Urinary Fumonisin B1 Excretion in Humans Consuming Maize-Based Diets . Molecular Nutrition and Food Research 56, 1445-1455.<br /> <br /> Riley, R.T., Voss, K.A., Coulombe, R.A. Jr., Pestka, J.J. and Williams, D.E. (2011) Developing Mechanism-Based and Exposure Biomarkers for Mycotoxins in Animals, in Determining Mycotoxins and Mycotoxigenic Fungi in Food and Feed, S. De Saeger (ed.), Ghent University, Woodhead Publishing Limited, Cambridge, U.K., Pp. 245-275.<br /> <br /> Riley, R.T., Voss, K.A., Coulombe, R.A., Pestka, J.J. and D. E. Williams (2011). Developing mechanism-based and exposure biomarkers for mycotoxins in animals. In Determining Mycotoxins and Mycotoxigenic Fungi in Food and Feed (S. De Saeger, ed.) Woodhead Publishing LTD, Cambridge, UK. ISBN 978-1-84569-674-0<br /> <br /> Riley, R.T., Voss, K.A., Showker, J.L., Torres, O., Matute, J., Maddox, J.R., Rainey, M.A., Gardner, N.M., Sachs, A., Gregory, S.G., Ashley-Koch, A.E., Krupp, D., and Gelineau-Van Waes, J. (2012) Development of Biomarkers to Assess Fumonisin Exposure and Birth Defects. In: World Nutrition Forum 2012, E.M. Binder, ed., pp 249-256, Anytime Publishing, Leicestershire, England.<br /> <br /> Romagnolo DF, Dashwood R, Stover PJ, Waterland RA, Ziegler TR. Nutritional regulation of epigenetic changes. Adv Nutr. 2012 Sep 1;3(5):749-50. doi: 10.3945/an.112.002675. <br /> <br /> Romagnolo DF, Davis CD, Milner JA. Phytoalexins in cancer prevention. Front Biosci. 2012 Jun 1;17:2035-58. Review. <br /> <br /> Romagnolo DF, Milner JA. Opportunities and challenges for nutritional proteomics in cancer prevention. J Nutr. 2012 Jul;142(7):1360S-9S. Epub 2012 May 30. PubMed PMID: 22649262; PubMed Central PMCID: PMC3374671.<br /> <br /> Romagnolo DF, Selmin OI. Flavonoids and cancer prevention: a review of the evidence. J Nutr Gerontol Geriatr. 2012;31(3):206-38. doi: 10.1080/21551197.2012.702534. PubMed PMID: 22888839.<br /> <br /> Shorey, L., Castro, D.J., Baird, W., Siddens, B., Löhr, Matzke, M., Waters, K., Corley, R.A. and Williams, D.E. (2012) Transplacental Carcinogenesis with Dibenzo[d,e,f,p]chrysene (DBC): Timing of Maternal Exposures Determines Target Tissue Response in Offspring. Cancer Lett. 317:49-55.<br /> <br /> Shorey, L.E., Hagman, A.M., Williams, D.E., Ho, E., Dashwood, R.H. and Benninghoff, A.D. (2012). 3,3-Diindolylmethane Induces G1 Arrest and Apoptosis in Human Acute T-Cell Lymphoblastic Leukemia Cells. PloS One 7:e34975.<br /> <br /> Shorey, L.E., Williams, D.E., Ho, E., Dashwood, R.H. and Benninghoff, A.D. (2012) 3,3-Diindolylmethane induces G1 arrest and apoptosis in human acute T-cell lymphoblastic leukemia cells. PLoS ONE 7(4): e34975. <br /> <br /> Siddens, L.K., Larkin, A., Krueger, S.K., Bradfield, C.A., Waters, K.M., Tilton, S.C., Pereira, C.B., Löhr, C.V., Arlt, V.M., Phillips, D.H., Williams, D.E. and Baird, W.M. (201x) PAHs as Skin Carcinogens: Comparison of Benzo[a]pyrene, Dibenzo[def,p]chrysene and Three Environmental Mixtures in the FVB/N Mouse. Toxicol. Appl. Pharmacol. 264:377-386.<br /> <br /> Sivapragasam, N.; Petrovi, D.; Thavarajah, D.; Thavarajah, P. (2013). Carbohydrate based micro- and nano-materials for functional food and pharmaceutical application<br /> <br /> Solhaug, A., Vines, L. L., Ivanova, L., Spilsberg, B., Holme, J. A., Pestka, J., Collins, A., and Eriksen, G. S. (2012). Mechanisms involved in alternariol-induced cell cycle arrest. Mutat Res. 738-739,1-11<br /> <br /> Tang, L., Yang, X., Dobrucki, W.L., Chaudhury, I., Yin, Q., Yao, C., Lezmi, S., Lu, Y., Helferich, W.G., Fan, T.M., and Cheng. J. Aptamer-functionalized, ultra-small, monodisperse silica nanoconjugate for targeted dual-modal imaging of lymph nodes with metastatic tumors. 2012. Angewandte Chemie. In Press.<br /> <br /> Turner, N. D. and J. R. Lupton (2011). "Dietary fiber." Adv Nutr 2(2): 151-152.<br /> <br /> Turner, P. C., Flannery, B., Isitt, C., Ali, M., and Pestka, J. (2012). The role of biomarkers in evaluating human health concerns from fungal contaminants in food. Nutr Res Rev 25, 162-179.<br /> <br /> Turner, R.T., Iwaniec, U.T., Olson, D.A., Branscum, A.J., Belosay, A., Wang, V.C., Neese, S.L., Andrade, J., Schantz, S.L., Doerge, D.R., Helferich, W.G. Physiologically Relevant Levels of Genistein Do Not Protect the Skeleton in Rat Models for Postmenopausal Bone Loss. 2012 (Submitted).<br /> <br /> Voss, K.A., Riley, R.T., Jackson, L.S., Jablonski, J.E., Bianchini, A., Bullerman, L.B., Hanna, M.A., Ryu, D. (2011) Extrusion cooking with glucose supplementation of fumonisin contaminated corn grits protected against nephrotoxicity and disrupted sphingolipid metabolism in rats. Molecular Nutrition and Food Research 55, S312-S320.<br /> <br /> Watterson, T.L., Hamilton, B., Martin, R., and R.A. Coulombe, Jr. (2012) Urban Particulate Matter Activates Akt in Human Lung Cells. Archives of Toxicology 86:121-135 DOI: 10.1007/s00204-011-0739-5.<br /> <br /> Watterson, T.L., Hamilton, B., Martin, R., and R.A. Coulombe, Jr. (2011) Urban Particulate Matter Activates Akt in Human Lung Cells. Archives of Toxicology DOI: 10.1007/s00204-011-0739-5<br /> <br /> Weir TL, Hu Y, Ryan EP, Lin W, Murray P, Fu D, Snook R, Xiao W. (2012) Medicinal teas: a review to summarize health benefits and highlight fermented tea. Herbalgram. 94: 45-49.<br /> <br /> WHO (2011) World Health Organization. Evaluation of Certain Food Additives and Contaminants. Seventy-fourth Report of the Joint FAO/WHO Expert Committee on Food Additives. WHO Technical report Series, no. 966, pp 136. (R.T. Riley Member of the Secretariat issuing the report)<br /> <br /> Williams, D.E. (2011) The Rainbow Trout Liver Cancer Model: Response to Environmental Chemicals and Studies on Promotion and Chemoprevention. Comp. Biochem. Physiol. Part C 155:121-127.<br /> Wu, W., Bates, M., Bursian, S. J., Link, J. E., Flannery, B. M., Sugita-Konishi, Y., Wantanabe, M., Zhang, H., and Pestka, J. J. (2012a). Comparison of emetic potencies of the 8-ketotrichothecenes deoxynivalenol, 15-acetyldeoxynivalenol, 3-acetyldeoxynivalenol, fusarenon x and nivalenol. Toxicol Sci.<br /> <br /> Wu, W., Flannery, B. M., Sugita-Konishi, Y., Watanabe, M., Zhang, H., and Pestka, J. J. (2012b). Comparison of murine anorectic responses to the 8-ketotrichothecenes 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, fusarenon X and nivalenol. Food Chem Toxicol 50, 2056-2061.<br /> <br /> Xing, H., Tang, L., Yang, X., Hwang, K., Wang, W., Yin, Q., Wong, N.Y., Dobrucki, L.W., Yasui, N., Katzenellenbogen, J.A., Helferich, W. Cheng, J., Lu, Y. Selective Delivery of an Anti-cancer Drug to Breast Cancers in Vitro and in Vivo with Nucleolin-Aptamer-Functionalized Liposomes. 2012 (Submitted).<br /> <br /> Xu X, Hu Y, Xiao W, Huang J, He X, Wu J, Ryan EP, Weir TL (2012) Effects of fermented Camilla sinensis, Fuzhuan tea, on egg cholesterol and production performance in laying hens. J. Int. Food and Agric. Res. 1:6-10.<br /> <br /> Yang, X., Belosay A., Hartman, J.A., Song H., Doerge D.R. and Helferich W.G., Estradiol increases ER± negative breast cancer metastasis in an experimental model. 2012. Clinical & Experimental Metastasis. In Press.<br />

Impact Statements

1. Collaborative research between W3122 and Indonesian scientists support the notion that certain microbes and plants are sources of potential therapeutic agents against cancer, immune deficiencies and neurological disorders. For additional information contact Len Bjeldanes (lfb@nature.berkeley.edu).
2. W3122 studies have shown that polyphenolic molecules influence the microbiota and their metabolism during chronic bouts of inflammatory bowel disease, and by so doing, they reduce the increase in injury caused in an animal model of the disease. For additional information contact Nancy Turner (n-turner@tamu.edu)
3. W3122 studies conducted in Guatemala in collaboration with the Centro de Investigaciones en Nutricion y Salud in Guatemala (CIENSA), Creighton University and Duke University are signifcant because every animal disease known to be caused by fumonisin has been shown to be closely correlated with and preceded by evidence of disruption of sphingolipid metabolism. The findings also provide a research tool for assessing the threshold for disruption of sphingolipid metabolism in humans and for designing epidemiological studies to evaluate the potential of fumonisin exposure as a contributing factor to human disease (For additional information contact Ronald T. Riley (ron.riley@ars.usda.gov).
4. Dietary chemoprevention of cancer by phytochemicals and determination of mechanisms of action by W3122 group has received a great deal of attention over the past year with numerous invitations to present at national/international meetings and academic institutions as well as stories for the popular media. For additional information contact David E. Williams (David.Williams@orst.edu).
5. To date there have not been studies reported on the role that the estradiol plays on breast cancer metastasis. W3122 researchers demonstrated that the estradiol can induce metastatic progression in a newly developed model of BC metastasis. For additional information contact William Helferich (helferic@uiuc.edu).
6. W3122 research on identifying features of the intestinal bacterial community associated with colon cancer could aid in development of new bacterial biomarkers for cancer diagnosis and monitoring of different treatment strategies, including dietary interventions. For example bran could be a low cost dietary strategy to improve mucosal immunity and intestinal health in developing countries where enteric pathogens are prevalent. Understanding how fuzhuan tea works to modulate lipid levels could lead to development of new food product such as low-cholesterol eggs, and result in complementary or alternative therapeutic uses of the tea for hypercholesterolemia, diabetes, and non-alcoholic fatty liver disease. For further information, contact Tiffany Weir (tiffany.weir@colostate.edu).
7. W3122 studies on the trichothecene mycotoxins will lead to improved understanding of the molecular basis by which trichothecenes affect obesity and growth. The data will directly inform regulators involve in human risk assessment thus enabling better management of the risks from DON to the U.S. public. This research will identify new targets for controlling the obesity pandemic. (For additional information, contact James Pestka (pestka@msu.edu).
8. W3122 studies support the hypothesis that transcriptional repression of BRCA-1 by the AhR involves promoter hypermethylation of a critical CpG regulatory region in the BRCA-1 gene and it is accompanied by the recruitment of chromatin remodeling factors. In contrast, resveratrol, selected as a prototype AhR antagonist, may prevent hypermethylation of a BRCA-1 CpG island reported to be hypermethylated in sporadic breast tumors. The fact many food constituents including phytoalexins and flavonoids possess ligand properties towards the AhR may offer new avenues for the development of prevention strategies for the prevention of tumor suppressor silencing in sporadic breast tumors. For additional information, contact Donato Romaglio (donato@ag.arizona.edu).
9. Carbohydrate based nano scale polymers are increasingly used in food and agricultural applications as they are biobased, degradable and poses less toxicity risks for humans and animals. For additional information, contact Donato Romaglio (donato@ag.arizona.edu).
10. Results of this study may help identify genetic markers which could be used to restore AFB1 resistance in domestic breeds, and may also shed light on the mechanisms of resistance to AFB1 in animals and humans. Characterizing genes such as CYPs and GSTs that are associated with mycotoxi sensitivity will allow identification of genomic determinants for resistance in humans and animals, thereby improving animal health and food safety. For further information, contact Roger Coulombe (Roger Coulombe <roger@usu.edu>).
11. Optimally-formulated rodent diets are not relevant to most human diets, especially for at-risk populations that frequently consume energy-dense, nutrient-poor foods. We believe that the new TWD for use in typical rodent colon cancer investigations may fill a critical void that is not addressed by using optimal basal diets that have little relevance to American dietary patterns. For further information, contact Abby Benninghoff (abby.benninghoff@usu.edu)
12. Results of in vitro experiments with DIM confirm that this bioactive food chemical is an effective suppressor of cancer cell growth in multiple T-ALL cell lines, which represent the heterogeneity of this disease. For additional information contact David E. Williams (David.Williams@orst.edu).

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Report Information

Participants

Roger Coulomb Utah State University
Abby D. Benninghoff Utah State University
Mike Harrington Colorado State University
Bill Helferich University of Illinois
Pratibha Nerurkar University of Hawaii
Marie-Louise Ricketts University of Nevada Reno
Elizabeth Ryan Colorado State University
Nancy Turner Texas A&M University
David Williams Oregon State University
Meijun Zhu University of Idaho

Brief Summary of Minutes

Brief Summary of Minutes of Annual Meeting

Dr. Roger Coulombe welcomed the assembly and reminded all participants that they should pay their $100 registration fee before the conclusion of the meeting or send directly to him ASAP.

 

Dr. Michael Harrington, Administrative Advisor, presented an overview of the USDA AFRI and multi-state programs, with several important highlights. These included:

• ESCOP Roadmap for Food and Agriculture


• Updates/changes to the AFRI program


• Key proposal & funding statistics

 

Participants provided 20-30 minute presentations detailing ongoing research activities and progress for W-3122 relevant objectives.

 

Business meeting to determine new officers, location of 2014 meeting, and discuss scientific confidentiality of unpublished projects presented.

 

Accomplishments

<p><strong>Objective 1: Determine the mechanisms by which dietary bioactive compounds protect against human diseases.</strong></p><br /> <p><strong>&nbsp;</strong></p><br /> <p>Pratibha Nerurkar and team (University of Hawaii) have recently demonstrated that bitter melon juice (BMJ) and <em>Morinda citrifolia</em> (noni) improves not only glucose and lipid metabolism, but also prevent weight gain in mice fed high-fat-diet (HFD) containing 58% fat. Mechanistic studies indicate a role for chronic inflammation in pathophysiology of cancer, obesity and T2D.</p><br /> <p>&nbsp;</p><br /> <p>Meijun Zhu and colleagues (Washington State University) have evaluated the protective effects of grape seed extract (GSE) on inflammatory bowel disease (IBD) symptoms and to further explore the underlying mechanisms using IL10-deficient mice. Though the etiology and pathogenesis of IBD remain poorly defined, the current understanding indicates that the pathogenesis of IBD might involve the defects in intestinal epithelial barrier.&nbsp; Up to now, pharmacological therapies for IBD long-term management rely on anti-inflammatory drugs, which can result in serious side effects, including secondary infections and immunosuppression. Grape seed extract (GSE) is a by-product of the wine industry, with abundant polyphenolic compounds known for their anti-inflammatory and anti-oxidative effects. They found that dietary GSE supplementation in a wild type and IL10 knockout mouse model did not affect food intake and body weight gain among treatments. GSE supplementation ameliorated IBD disease indices in IL10KO mice. They analyzed gut epithelial barrier function, and found that the colonic goblet cell density of IL10KO mice was numerically lower than that of WT mice, while GSE supplementation increased goblet cell density in both WT and IL10KO mice. Consistently, claudin2, a pore forming tight junction protein, were reduced in both GSE fed WT and IL10KO mice. Compared to WT-CON mice, GSE supplementation also minimized t splenomegaly in IL10KO mice. Concomitantly, GSE supplementation attenuated inflammation and neutrophil infiltration in IL10KO mice. Furthermore, GSE supplementation increased the abundance of <em>Lactobacilli </em>and <em>Bacteroides </em>in gut microbiota of IL10KO mice. In conclusion, results demonstrated that dietary GSE supplementation exerts protective effects in IBD indices of IL10KO mice through multiple mechanisms.</p><br /> <p>&nbsp;</p><br /> <p>Dave Williams and his team (Oregon State University) continue to research dietary chemoprevention of cancer, specifically protection of the fetus/infant from transplacental carcinogens by dietary supplementation with plant phytochemicals or the whole foods from which they were derived. The emphasis continues to be on phytochemicals from cruciferous vegetables primarily indole-3-carbinol (I3C) and sulforaphane (SFN).</p><br /> <p>&nbsp;</p><br /> <p>Tiffany Weir, Elizabeth Ryan and colleagues (Colorado State University) have shown that intestinal microbes and their metabolites are an important factor modulating intestinal inflammation and development of CRC. Rice bran has a number of phytochemical components that contribute to its reported anti-inflammatory and anti-carcinogenic bioactivities and has the potential to be incorporated as a dietary component for chemoprevention. Pilot feasibility in a healthy population and initial analysis of a CRC cohort suggest that incorporation of rice bran does not cause a large-scale disturbance in the intestinal ecosystem, but rather induces subtle changes to the microbiota and metabolites detected in stool samples. The changes they observed include increases in certain beneficial commensal bacteria and the introduction of bioactive metabolites reduce inflammation and contribute to CRC chemoprevention. Initial microbiota analysis have revealed that rice bran consumption significantly increased the probiotic bacteria, <em>Bifidobacterium,</em> as well as increasing several butyrate-producing bacterial species such as <em>Paraprevotella</em> and <em>Ruminococcus</em> . This is relevant to chemoprevention as <em>Bifidobacterium</em> is important in modulation of innate and adaptive immune responses and butyrate has been shown to have anti-inflammatory and anti-proliferative effects and feeds colonic epithelium.</p><br /> <p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</p><br /> <p>&nbsp;</p><br /> <p>Nancy Turner and colleagues (Texas A&amp;M) have demonstrated that butyrate influences histone acetylation and DNA promoter methylation, and through these effects is capable of altering expression of key genes involved in regulating colonocyte physiology. They have also shown that polyphenolic molecules derived from certain varieties of sorghum grain can influence colonic microbiota and metabolism during chronic bouts of inflammatory bowel disease, and by so doing, they reduce the increase in injury caused in an animal model of the disease. Importantly, these effects have been translated into a human study where they have observed alterations in microbial populations and their metabolites found in systemic circulation of overweight subjects.</p><br /> <p>Dr. Benninghoff and colleagues (Utah State University) in the Applied Nutrition Research Group have developed and are testing a new rodent diet that models typical Western nutrition. Rodent cancer studies typically use defined diets with nutrient profiles optimized for rodent health. However, a defined rodent diet that represents typical American nutrition in all aspects, including calorie sources and macro- and micronutrient composition, was not available. Thus, they used a nutrient density approach to formulate the new Total Western Diet (TWD) based on NHANES data for macro- and micronutrient intakes. The new diet contains more saturated and monounsaturated fats, less polyunsaturated fat, more complex carbohydrates and twice the level of simple sugars.&nbsp; The TWD includes less calcium, copper, folate, thiamine and vitamins B₆, B₁₂, D and E, but much more sodium.&nbsp; This newly devised diet that better represents typical American nutrition will be highly useful for studies employing animal models of human disease, including cancer.&nbsp; As proof of principle, they employed the azoxymethane (AOM) model of colorectal cancer in mice fed either TWD or AIN93G basal diets supplemented with or without green tea extract in the drinking water. Green tea extract reduced body fat percentage in both the TWD and AIN93G groups and decreased fasting glucose levels in mice fed TWD but not AIN93G. Mice fed TWD without green tea had more aberrant crypt foci and a higher total crypt cell count compared to cohorts fed the AIN93G diet and responded better to green tea extract. These results suggest that the Western dietary pattern promotes carcinogenesis and that supplementation with chemopreventive bioactives may be beneficial to populations consuming a poor diet.&nbsp;</p><br /> <p>&nbsp;</p><br /> <p>Roger Coulombe and colleagues (Utah State University) showed that dietary indole-3-carbinol (I3C) is an effective transplacental chemopreventive agent in a dibenzo[<em>def,p</em>]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. Certain bioactive food components, including I3C and 3,3&rsquo;-diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. They extended previous chemoprevention studies in mice to an analogous human neoplasm in cell culture, testing the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells.&nbsp; Treatment of several T-ALL cell lines with DIM <em>in vitro</em> significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C.&nbsp; DIM arrested CEM and HSB2 cells at the G₁ phase of the cell cycle and significantly increased the percentage of apoptotic cells in all T-ALL lines.&nbsp; In the CEM cell line, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis. Similar anticancer effects of DIM were observed <em>in vivo</em>.&nbsp; Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice.&nbsp; Taken together, our results demonstrate a potential for therapeutic application of DIM in T-ALL.</p><br /> <p>&nbsp;</p><br /> <p>Dave Pagliarini and colleagues (University of Wisconsin) has continued to investigate the effects of iron deprivation on the cellular control of mitochondrial biogenesis. The discovered, using microarray and quantitative mass-spectrometry approaches, that depriving mouse myotubes of iron, through treatment with the iron chelator deferoxamine (DFO) leads to a global decrease in the transcript abundance of mitochondrial- and nuclear-encoded mitochondrial genes and mitochondrial proteins. They have found that this response to iron chelation is universal across a broad range of cell types, rapid and dose-dependent. Additionally, they discovered that the effect on cellular gene expression and respiratory capacity can be fully reversed upon the reintroduction of iron, indicating that the response to iron deprivation is an adaptive cellular response rather than irreversible cellular damage. Lastly, they showed that this process is independent of well-established regulators of mitochondrial biogenesis, including PGC-1&alpha;, PGC-1&beta; and HIF-1&alpha;. They have continued to elucidate the molecular basis of this adaptive cellular response by performing detailed timecourse measurements of mitochondrial transcript and protein levels following iron deprivation, and found that the decrease in oxidative phosphorylation proteins preceded the decrease in their corresponding transcripts. These results suggest that the changes in mitochondrial transcript and protein levels occur though two separate mechanisms <em>or</em> that the changes in transcript abundance are in response to the protein changes.</p><br /> <p>&nbsp;</p><br /> <p>&nbsp;</p><br /> <p><strong>Objective 2: Elucidate mechanisms of action of dietary toxicants and develop biomarkers for human risk assessment and disease prevention. </strong></p><br /> <p>Dave Williams and colleagues (Oregon State University) currently focuses on mechanisms of action and biomarkers associated with an important class of environmental chemicals of concern, polycyclic aromatic hydrocarbons (PAHs), of food-borne carcinogens. Their research has included identification of molecular biomarkers such as alterations in levels of tumor suppressor genes, DNA adductions, etc., in addition to biological endpoints.</p><br /> <p>Roger Coloumbe and colleagues (Utah State University) focused his efforts on identifying which GST gene(s) are responsible for protection against AFB₁. Unlike their more susceptible counterparts, wild turkeys possess functional hepatic GSTs with AFB₁ detoxification activity.&nbsp; Given that alpha-class GSTs are the likely candidates from rodent models, they expressed, cloned and functionally characterized six GSTA genes from the livers of wild and domestic turkeys.&nbsp; In contrast to their hepatic forms, all <em>E. coli</em>-expressed recombinant GSTAs from both domestic and wild turkeys, had AFBO-detoxification activity. This implies that hepatic GSTs in domestic turkeys are downregulated by one or more genetic or epigenetic mechanisms.&nbsp; Focused sequencing of the hepatic transcriptome revealed significantly more hepatic GSTAs are expressed in wild than domestic birds, a difference more marked for two genes - GSTA3 and GSTA4. As in isolated populations of people with cancer susceptibility due to GST polymorphisms, loss of protective GST alleles in domestic turkeys is the likely mechanism for their extreme sensitivity compared to wild birds, fulfilling predictions that genetic improvement, domestication, and industry consolidation of commercial poultry result in the loss of genetic diversity, species fitness, and often, enhanced susceptibility to pathogens and environmental agents.</p><br /> <p>&nbsp;</p><br /> <p>Mendel Friedman and colleagues (USDA-California) developed quantitative methods for the detection of biologically active aflatoxin B₁ (AFB1) in Vero cells. Aflatoxin-producing fungi contaminate food and feed during storage and processing periods. Once consumed, aflatoxins (AFs) accumulate in tissues, causing illnesses in animals and humans. The policy of blending and dilution of grain containing higher levels of aflatoxins with uncontaminated grains for use in animal feed implicitly assumes that the deleterious effects of low levels of the toxins are linearly correlated to concentration. This assumption may not be justified, since it involves extrapolation of these nontoxic levels in feed, which are not of further concern. To develop a better understanding of the significance of low dose effects, they developed quantitative methods for the detection of aflatoxin B₁ (AFB1) by two independent assays: the green fluorescent protein (GFP) assay, as a measure of protein synthesis by the cells, and the microculture tetrazolium (MTT) assay, as a measure of cell viability. The results demonstrate a non-linear dose-response relationship at the cellular level. AFB1 at low concentrations has an opposite biological effect to higher doses that inhibit protein synthesis.</p><br /> <p>&nbsp;</p><br /> <p>Ron Riley and team (USDA-Georgia) conducted a second human study (HS2) that indicated a significant correlation between urinary FB1 (UFB1) and elevation in the blood sphinganine 1-phosphate/sphingosine 1-phosphate ratio, a result consistent with the conclusion that FB exposure led to disruption of sphingolipid metabolism in humans. A Human Study 3 (HS3) was begun with a survey of fumonisin contamination in maize across Guatemala which was initiated in May 2012 and completed in October 2012.&nbsp; A total of 640 maize samples from all 22 departments were analyzed for both fumonisin and aflatoxins. Very high levels of aflatoxins and fumonisin were detected in maize from the Department of Pet&eacute;n.&nbsp; High levels of fumonisin, but not aflatoxins, were also detected in the Departments of Chiquimula and Santa Rosa and very low levels of fumonisin and aflatoxin were detected in the highland Department of Sacatep&eacute;quez.&nbsp; An additional low and two high FB exposure departments were also selected based on the results of the maize survey, Sacatepequez (low fumonisin exposure), Chiquimula (high fumonisin exposure) and Santa Rosa (high fumonisin exposure). Human blood (n=390), urine (n=390) and corn (n=30) for human consumption were collected in February and March 2013 and analyzed for UFB1, sphingoid base 1-phosphates and FB, respectively.&nbsp; The FB analysis of the maize and the UFB1 levels confirm low exposure in Sacatepequez and high exposure in Chiquimula and Santa Rosa.&nbsp; The ratio of sphinganine 1-phosphate/sphingosine 1-phosphate and the levels of sphinganine 1-phosphate in the blood are significantly correlated with the UFB1 levels. Results thus far are consistent with the conclusion that FB exposure can led to elevation in sphinganine 1-phosphate in blood as a consequence of fumonisin inhibition of ceramide synthase in tissues.&nbsp; The UFB1 and blood sphingoid base-1-phosphate data that we have accumulated should allow us to predict a window of UFB1 that increases the relative risk for fumonisin exposure-induced disruption of sphingolipid metabolism in humans.</p><br /> <p>&nbsp;</p><br /> <p>&nbsp;</p><br /> <p><strong>&nbsp;</strong></p><br /> <p><strong>Objective 3: Discover and characterize novel dietary compounds that have beneficial or adverse effects on human health. </strong></p><br /> <p>&nbsp;</p><br /> <p>Marie Louise Ricketts and colleagues (University of Nevada) has extended their investigation into the modulation of FXR-target genes in the small intestine and liver by a grape seed procyanidin extract (GSPE). Studies initially focused on the effects of GSPE on known intestinal FXR target genes in Caco2 cells, namely apical sodium dependent bile acid transporter (ASBT), ileal bile acid binding protein (IBABP), fibroblast growth factor 15/19 (FGF15/19) and organic solute transporters alpha and beta. They have expanded their studies <em>in vivo </em>using C57BL/6 wild type mice. Their results show that GSPE differentially modulates FXR-target genes ultimately altering enterohepatic bile acid recirculation in both the intestine and liver. GSPE-mediated alterations in gene expression result in impairment of intestinal BA up-take and decrease the amount of BA that return to the liver via the portal circulation; an observation supported by a significant reduction in serum bile acid levels following GSPE administration. They hypothesize that the impairment in bile acid absorption caused by GSPE administration may represent another mechanism involved in its&rsquo; hypotriglyceridemic effect.</p><br /> <p>&nbsp;</p><br /> <p>Mendel Friedman and colleagues (USDA-California) examined the antitumor effects of dietary black and brown rice brans in tumor-bearing mice. Black and brown rice brans from <em>Oryza sativa</em> LK1-3-6-12-1 and Chuchung cultivars each contained 21 compounds characterized by GC/MS. Mice fed diets with added rice brans for 2 weeks were intracutaneously inoculated with CT-26 mouse cancer cells and fed the same diet for two additional weeks. Tumor mass was 35% and 19% lower in the black and brown bran-fed groups, respectively. Tumor inhibition was associated with increases in cytolytic activity of splenic natural killer (NK) cells; partial restoration of nitric oxide production and phagocytosis in peritoneal macrophages; increases in released tumor necrosis factor-&alpha;, IL-1&beta;, and IL-6 from macrophages; increases in infiltration of leukocyte into the tumor; and reduction in angiogenesis inside the tumor. Proangiogenic biomarkers vascular endothelial growth factor, cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX) were also reduced in mRNA and protein expression. ELISA of tumor cells confirmed reduced expression of COX-2 and 5-LOX. Reduced COX-2 and 5-LOX expression downregulated vascular endothelial growth factor and inhibited neoangiogenesis inside the tumors. Induction of NK activity and macrophages and inhibition of angiogenesis seem to contribute to tumor regression.</p><br /> <p>Mendel Friedman and colleagues (USDA-California) also explores how<em> Hericium erinaceus</em> (Lion's Mane) mushroom extracts inhibit metastasis of cancer cells to the lung in CT-26 colon cancer-transplanted mice.&nbsp; They investigated the antimetastatic activity of four <em>Hericium erinaceus</em> edible mushroom extracts using CT-26 murine colon carcinoma cells as an indicator of inhibition of cell migration to the lung. Hot water (HWE) and microwaved 50% ethanol (MWE) extracts of <em>H. erinaceus</em> strongly elicited cancer cell death through apoptosis and inhibited metastasis of cancer cells to the lungs by 66% and 69%, respectively. HWE and MWE reduced the expression of matrix metalloproteinases MMP-2 and MMP-9 in cells and their activities in culture media. Urokinase-type plasminogen activator (u-PA), another extracellular matrix (ECM)-degrading proteinase, also showed decreased protein expression. In CT-26 cells, HWE and MWE down-regulated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) phosphorylations. The reduced phosphorylations seem to cause reduction of activity of the MMPs, thereby blocking migration and invasion of cells. Dietary administration of HWE and MWE reduced the formation of tumor nodules in the lung by about 50% and 55%, respectively, and prevented increases in lung weight caused by cancer cell metastasis. These results demonstrate the effectiveness of HWE and MWE as beneficial antimetastatic agents, targeting their upstream signaling molecules for mediating the expression of the ECM-degrading proteinases.</p><br /> <p>&nbsp;</p><br /> <p><strong>Objective 4: Increase beneficial or decrease adverse effects of bioactive constituents and microbes in food. </strong></p><br /> <p><strong>&nbsp;</strong></p><br /> <p>Mendel Friedman and colleagues (USDA-California) investigated the combined effect of three internal temperatures and different concentrations of sodium chloride (NaCl) and apple polyphenols (APP), individually and in combination, on the heat-resistance of a five-strain cocktail of <em>Listeria monocytogenes</em> in ground beef. Mathematical models were used to quantitate the combined effect of these parameters on heat resistance of the pathogen. The theoretical analysis shows that compared with heat alone, the addition of NaCl enhanced and that of APP reduced the heat resistance of <em>L. monocytogenes</em>. By contrast, the protective effect of NaCl against thermal inactivation of the pathogen was reduced when both additives were present in combination, as evidenced by reduction of up to ~68%. The observed high antimicrobial activity of the combination of APP and low salt suggests that commercial and home processors of meat could reduce the salt concentration by adding APP to the ground meat. The influence of the combined effect allows a reduction of the temperature of heat treatments as well as the salt content of the meat.</p><br /> <p>This research team (Friedman, USDA-California) also evaluated the effectiveness of oregano and cinnamon essential oils and powdered olive and apple extracts against different types of Salmonella bacteria that can present as food contaminants. All tested plant compounds showed efficacy against Salmonella under different conditions and may be suitable to enhance the microbial safety of ground pork, leafy green vegetables, and other food products that are susceptible to contamination with this pathogen.</p><br /> <p>Dave Williams (Oregon State University) has focused on reducing human health risks from food-borne pathogens and environmental contaminants. Indole -3 carbinol (I3C) is especially potent in reducing the risk to the fetus from exposure <em>in utero</em> to chemical carcinogens ingested in food.&nbsp;</p><br /> <p><strong>Impact Statements: </strong></p><br /> <ol><br /> <li>W3122 researchers are identifying appropriate genetic markers for the AFBO-trapping GST allele in wild turkeys. Once identified resistance can be reintroduced into domestic turkeys by backcrossing. An AFB1-resitant turkey would help save the poultry industry millions of dollars lost each year due to contaminating aflatoxins in feeds. For additional information contact Roger Coloumbe (<a href="mailto:roger@usu.edu">roger@usu.edu</a>)</li><br /> <li>W3122 researchers are looking at unique whole food, food component and phytochemical profiles to reduce food-borne pathogen loads and improve health. For additional information contact Mendel Friedman (<a href="mailto:Mendel.Friedman@ARS.USDA.GOV">Mendel.Friedman@ARS.USDA.GOV</a>)</li><br /> <li>W3122 researchers have identified bitter melon juice as a culturally appropriate dietary intervention to control breast cancer and T2D among ethnic minorities in Hawaii. For more information contact Pratibha Nerurkar (<a href="mailto:Pratibha@hawaii.edu">Pratibha@hawaii.edu</a>)</li><br /> <li>W3122 researchers are looking for new ways to combat iron deficiency by examining molecular mechanisms that regulate mitochondrial biogenesis during iron deprivation. Moreover, elucidating mechanisms of mitochondrial alteration may provide valuable insight into disease pathogenesis, as mitochondrial dysfunction occurs in diabetes, cancer, and age-related disorders. For more information contact Dave Pagliarini (<a href="mailto:Pagliarini@wisc.edu">Pagliarini@wisc.edu</a>)</li><br /> <li>W3122 researchers are unraveling the complexities underlying the molecular actions of bioactive dietary components by providing evidence of a new molecular mechanism contributing to the triglyceride-lowering ability of this grape seed extract. For more information contact Marie-Louise Ricketts (<a href="mailto:mricketts@cabnr.unr.edu">mricketts@cabnr.unr.edu</a>)</li><br /> <li>W3122 have shown in human studies that Fumosin B (FB) exposure (based on the UFB1), is significantly correlated with the Sa1P/So1P ratio and the increased level of Sa1P in blood spots, supporting the hypothesis that exposure to high levels of FB in humans disrupts sphingolipid metabolism through inhibition of ceramide synthase. This is a significant finding because every animal disease known to be caused by FB is closely correlated with evidence of disruption of sphingolipid metabolism. Being able to predict the level of FB intake that is likely to result in disruption in sphingolipid metabolism is an important first step for defining any possible role for FB as a contributing factor to the increased neural tube defect risk in areas where maize is a dietary staple. For more information contact Ron Riley (<a href="mailto:ron.riley@ars.usda.gov">ron.riley@ars.usda.gov</a>)</li><br /> <li>W3122 researchers have demonstrated that butyrate influences histone acetylation and DNA promoter methylation, and through these effects is capable of altering expression of key genes involved in regulating colonocyte physiology. They have also shown that polyphenolic molecules derived from certain varieties of sorghum grain can influence colonic microbiota and metabolism during chronic bouts of inflammatory bowel disease, and by so doing, they reduce the increase in injury caused in an animal model of the disease. These effects have been translated into a human study where they have observed alterations in microbial populations and their metabolites found in systemic circulation of overweight subjects. For more information contact Nancy Turner (<a href="mailto:n_turner@tamu.edu">n_turner@tamu.edu</a>)</li><br /> <li>W3122 researchers have identified rice bran as a feasible dietary intervention for the prevention of recurrence of colorectal cancer. They are also identifying external (total diet intake) and intrinsic (genetic make-up, microbial community structure) host factors that can be used in predicting individual response to diet interventions. For more information contact Tiffany Weir (<a href="mailto:Tiffany.weir@colostate.edu">Tiffany.weir@colostate.edu</a>)</li><br /> <li>W3122 researchers have garnered national and international media attention for studies on dietary chemoprevention of cancer by phytochemicals and determination of mechanisms of action. For more information contact Dave Williams (dave.williams@orst.edu)</li><br /> <li>W3122 researchers have demonstrated that dietary grape seed extract supplementation exerts protective effects in IBD indices of IL10KO mice through multiple mechanisms and may have importance as a human therapeutic for IBD. For more information contact Meijun Zhu (<a href="mailto:mzhu@uidaho.edu">mzhu@uidaho.edu</a>)</li><br /> </ol>

Publications

<p><strong>Publications:</strong></p><br /> <p>Kim, J.E., Bunderson, B., Croasdell, A., Reed, K.M, and <span style="text-decoration: underline;">R.A. Coulombe, Jr.</span> (2013) Alpha-class glutathione S-transferases in Wild Turkeys: Characterization and Role in Resistance to the Carcinogenic Mycotoxin Aflatoxin B1. <em>PLOS One</em> 8(4): e60662. <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0060662?utm_source=feedburner&amp;utm_medium=feed&amp;utm_campaign=Feed%3A+plosone%2FPLoSONE+%28PLoS+ONE+Alerts%3A+New+Articles%29">doi:10.1371/journal.pone.0060662</a></p><br /> <p>Bunderson, B., Kim, J.E., Croasdell, A., Mendoza, K, Reed, K.M, and <span style="text-decoration: underline;">R.A. Coulombe, Jr</span>. (2013) Heterologous Expression and Functional Characterization of Avian Mu-Class Glutathione S-Transferases. <em>Comp. Biochem. Physiol. C &ndash; Toxicol Pharmacol</em>. 158: 109-116. <a href="http://www.ncbi.nlm.nih.gov/pubmed/23712008">DOI: 10.1016/j.cbpc.2013.05.007</a>.</p><br /> <p>Wu, Y., McEwen, G.D., Tang, M., Yu, T., Dimmick, Zhou, A., Gilbertson, T.A., <span style="text-decoration: underline;">Coulombe, Jr., R.A.</span>, and J.R. Stevens. (2013) Sensing Biophysical Alterations of Human Lung Cells (A549) in the Context of Toxicity Effects of Diesel Exhaust Particles. <em>Cell Biochem Biophys </em>May 28 (epub ahead of print) <a href="http://www.ncbi.nlm.nih.gov/pubmed/23712864">DOI: 10.1007/s12013-013-9618-4</a></p><br /> <p>Watterson, T.L., Hamilton, B., Martin, R., and <span style="text-decoration: underline;">R.A. Coulombe, Jr.</span> (2012) Urban Particulate Matter Activates <em>Akt</em><em>&nbsp;</em>in Human Lung Cells. <em>Archives of Toxicology </em>86:121-135 <a href="http://www.ncbi.nlm.nih.gov/pubmed/21818627">DOI: 10.1007/s00204-011-0739-5</a></p><br /> <p><span style="text-decoration: underline;">Benninghoff, A.D</span>.* and Williams, D.E. (2013) The role of estrogen receptor beta (ER&beta;) in transplacental cancer prevention by indole-3-carbinol.&nbsp; Cancer Prevention Research 6(4): 339-348.</p><br /> <p>Chen CH, Ravishankar S, Marchello J, <span style="text-decoration: underline;">Friedman M</span>. 2013. Antimicrobial activity of plant compounds against <em>Salmonella </em>Typhimurium DT104 in ground pork and the influence of heat and storage on the antimicrobial activity. J Food Prot 76(7):1264-9.</p><br /> <p>Choi S-H, Ahn J-B, Kim H-J, Im N-K, Kozukue N, Levin CE, <span style="text-decoration: underline;">Friedman M</span>. 2012. Changes in free amino acid, protein and flavonoid content in jujube (<em>Ziziphus jujube</em>) fruit during eight stages of growth and antioxidative and cancer cell inhibitory effects by extracts. J Agric Food Chem 60(41):10245-55.</p><br /> <p>Choi SP, Kim SP, Nam SH, <span style="text-decoration: underline;">Friedman M</span>. 2013. Antitumor effects of dietary black and brown rice brans in tumor-bearing mice: Relationship to composition. Mol Nutr Food Res 57(3):390-400.</p><br /> <p>Du W-X, Avena-Bustillos RJ, Woods RD, Breksa A, McHugh TH, <span style="text-decoration: underline;">Friedman M</span>, Levin CE, Mandrell R. 2012. Sensory evaluation of baked chicken wrapped with antimicrobial apple and tomato edible films formulated with cinnamaldehyde and carvacrol. J Agric Food Chem 60(32):7799-804.</p><br /> <p><span style="text-decoration: underline;">Friedman M</span>. 2013. Review of the anticarcinogenic, cardioprotective, and other health benefits of tomato compounds lycopene, a-tomatine, and tomatidine in pure form and in fresh and processed tomatoes. J Agric Food Chem. 2013, Online; DOI.org/10.1021/jf402654e</p><br /> <p><span style="text-decoration: underline;">Friedman M</span>, Henika PR, Levin CE. 2013. Bactericidal activities of health-promoting, food-derived powders against the foodborne pathogens <em>Escherichia coli</em>, <em>Listeria monocytogenes</em>, <em>Salmonella enterica</em>, and <em>Staphylococcus aureus</em>. J Food Sci 78(2):M270-M5.</p><br /> <p><span style="text-decoration: underline;">Friedman M</span>, Rasooly R. 2013. Review of the inhibition of biological activities of food-related selected toxins by natural compounds. Toxins 5(4):743-75.</p><br /> <p>Juneja VK, Altuntas EG, Ayhan K, Hwang C-A, Sheen S, <span style="text-decoration: underline;">Friedman M</span>. 2013. Predictive model for the reduction of heat resistance of <em>Listeria monocytogenes </em>in ground beef by the combined effect of sodium chloride and apple polyphenols. Int J Food Microbiol 164(1):54-9.</p><br /> <p>Juneja VK, Gonzales-Barron U, Butler F, Yadav AS, <span style="text-decoration: underline;">Friedman M</span>. 2013. Predictive thermal inactivation model for the combined effect of temperature, cinnamaldehyde and carvacrol on starvation-stressed multiple <em>Salmonella </em>serotypes in ground chicken. Int J Food Microbiol 165(2):184-99.</p><br /> <p>Kim SP, Nam SH, <span style="text-decoration: underline;">Friedman M</span>. 2013. <em>Hericium Erinaceus </em>(Lion's Mane) mushroom extracts inhibit metastasis of cancer cells to the lung in CT-26 colon cancer-transplanted mice. J Agric Food Chem 61(20):4898-904.</p><br /> <p>Moore-Neibel K, Gerber C, Patel J, <span style="text-decoration: underline;">Friedman M</span>, Jaroni D, Ravishankar S. 2013. Antimicrobial activity of oregano oil against antibiotic-resistant <em>Salmonella enterica </em>on organic leafy greens at varying exposure times and storage temperatures. Food Microbiol 34(1):123-9.</p><br /> <p>Rasooly R, Hernlem B, <span style="text-decoration: underline;">Friedman M</span>. 2013. Low levels of aflatoxin B1, ricin, and milk enhance recombinant protein production in mammalian cells. PLoS ONE 8(8):article no. e71682; doi:10.1371/journal.pone.0071682.</p><br /> <p>Rasooly R, Hernlem B, He X, <span style="text-decoration: underline;">Friedman M</span>. 2013. Non-linear relationships between aflatoxin B1 levels and the biological response of monkey kidney Vero cells. Toxins 5(8):1447-61.</p><br /> <p>Rounds L, Havens CM, Feinstein Y, <span style="text-decoration: underline;">Friedman M</span>, Ravishankar S. 2013. Concentration-dependent inhibition of <em>Escherichia coli </em>O157:H7 and heterocyclic amines in heated ground beef patties by apple and olive extracts, onion powder and clove bud oil. Meat Sci 94(4):461-7.</p><br /> <p>Todd J, <span style="text-decoration: underline;">Friedman M</span>, Patel J, Jaroni D, Ravishankar S. 2013. The antimicrobial effects of cinnamon leaf oil against multi-drug resistant <em>Salmonella </em>Newport on organic leafy greens. Int J Food Microbiol 166(1):193-9.</p><br /> <p>Rajamoorthi A, Shrivastava S, Steele R, <span style="text-decoration: underline;">Nerurkar P</span>, Gonzalez JG, Crawford S, Varvares M and Ray RB. Bitter Melon Reduces Head and Neck Squamous Cell Carcinoma Growth by Targeting c-Met Signaling. <em>PLoS One</em>. 2013 Oct 17;8(10):e78006. doi: 10.1371/journal.pone.0078006.</p><br /> <p>Rensvold JW, Ong SE, Jeevananthan A, Carr SA, Mootha VK and <span style="text-decoration: underline;">Pagliarini DJ</span>, Complementary RNA and Protein Profiling Identifies Iron as a Key Regulator of Mitochondrial Biogenesis. Cell Reports, 2013, 3(1): 237-245.</p><br /> <p>Caiozzi G, Wong BS, <span style="text-decoration: underline;">Ricketts ML.</span> <a href="http://www.ncbi.nlm.nih.gov/pubmed/23027406"><em>Dietary modification of metabolic pathways via nuclear hormone receptors.</em></a><em>C</em><em>el</em><em>l Biochem Funct. (2012) 30(7):531-51. </em>doi: 10.1002/cbf.284</p><br /> <p>Bondy, G.S., Mehta, R., Caldwell, D., Coady, L., Armstrong, C., Savard, M., Miller, J. D., Chomyshyn, E., Bronson, R., Zitomer, N.C., <span style="text-decoration: underline;">Riley, R.T</span>. (2012) Effects of long term exposure to the mycotoxin fumonisin B₁ in p53 heterozygous and p53 homozygous transgenic mice. Food and Chemical Toxicology. 50 (10), 3604-3613. <em>(reported last year but without volume and pages)</em></p><br /> <p>Gelineau-van Waes, J., Rainey, M.A., Maddox, J. R., Voss, K. A., Sachs, A. J., Gardner, N. M., Wilberding, J. D. and <span style="text-decoration: underline;">Riley, R. T</span>. (2012) Increased sphingoid base-1-phosphates and failure of neural tube closure after exposure tofumonisin or FTY720. Birth Defects Research Part A: Clinical and Molecular Teratology 94(10), 790-803. <em>(reported last year but without volume and pages)</em></p><br /> <p>Pitt, J.I., Wild, C.P., Gelderblom, W.C.A., Miller, J.D., <span style="text-decoration: underline;">Riley, R.T.,</span> Wu, F. and Baan, R.A. (Eds). (2012).&nbsp; Management Of Mycotoxins In Foods And Feeds For Improving Public Health.&nbsp; 165 pp., International Agency for Research on Cancer Scientific Publication No 158, Lyon, France.</p><br /> <p>Van der Westhuizen, L., Shephard, G. S., Gelderblom, W. C. A., Torres, and <span style="text-decoration: underline;">Riley, R.T.</span> (2013) Fumonisin biomarkers in maize eaters and implications for human disease. World Mycotoxin Journal 6(3):223-232.</p><br /> <p>Voss, K.A., <span style="text-decoration: underline;">Riley, R.T.,</span> Moore, N.D., Burns, T.D. (2013) Alkaline cooking (Nixtamalization) reduced the in vivo toxicity of fumonisin-contaminated corn in a rat feeding bioassay. Food Additives and Contaminants. 30, 1415-1421.</p><br /> <p>Cho, Y., <span style="text-decoration: underline;">N.D. Turner, </span>L.A. Davidson, R.S. Chapkin, R.J. Carroll, and J.R. Lupton.&nbsp; 2012.&nbsp; A chemoprotective fish oil/pectin diet enhances apoptosis via Bcl-2 promoter methylation in rat azoxymethane-induced carcinomas.&nbsp; Experimental Biology &amp; Medicine 237:1387-1393.</p><br /> <p><span style="text-decoration: underline;">Turner, N.D</span>., L.E. Ritchie, R.S. Bresalier, and R.S. Chapkin.&nbsp; The microbiome and colorectal neoplasia &ndash; environmental modifiers of dysbiosis.&nbsp; Current Gastroenterology Reports 15(9):346.</p><br /> <p><span style="text-decoration: underline;">Weir TL*</span>, Manter DK, Sheflin AM, Barnett BA, Heuberger AH, Ryan EP (2013) Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. <em>PLoS One. PLoS One </em>8(8): e70803. doi:10.1371/journal.pone.0070803</p><br /> <p>Keller AC, <span style="text-decoration: underline;">Weir TL*</span>, Broeckling CD, Ryan EP (2013) Antibacterial activity and phytochemical profile of fermented <em>Camellia sinensis</em> (Fuzhuan tea).<em> Food Research International. dx.doi.org/10.1016/j.foodres/2013.04.023</em></p><br /> <p>Borresen EC, Henderson AJ, Kumar A, <span style="text-decoration: underline;">Weir TL</span>, Ryan EP (2012) Fermented foods: Patented approaches and formulations for nutritional supplementation and health promotion. <em>Recent Patents on Food, Nutrition &amp; Agriculture. 4,</em><em>134-140.</em></p><br /> <p>Xu X, Hu Y, Xiao W, Huang J, He X, Wu J,&nbsp; Ryan EP, <span style="text-decoration: underline;">Weir TL</span>* (2012) Effects of fermented <em>Camilla sinensis</em>, Fuzhuan tea, on egg cholesterol and production performance in laying hens. <em>J. Int. Food and Agric. Res. </em>1:6-10.</p><br /> <p>Parasramka, M.A., Dashwood, W.M., Wang, R., Saeed, H.H., <span style="text-decoration: underline;">Williams, D.E.,</span> Ho, E. and Dashwood, R.H. (2012) A Role for Low-Abundance miRNAs in Colon Cancer: the miR-206/Kr&uuml;ppel-Like Factor 4 (KLF4) Axis.&nbsp; Clin. Epigenetics. 4:16 DOI: 10.1186/1868-7083-4-16.</p><br /> <p>Siddens, L.K., Larkin, A., Krueger, S.K., Bradfield, C.A., Waters, K.M., Tilton, S.C., Pereira, C.B., L&ouml;hr, C.V., Arlt, V.M., Phillips, D.H., <span style="text-decoration: underline;">Williams, D.E</span>. and Baird, W.M. (2012) PAHs as Skin Carcinogens: Comparison of Benzo[a]pyrene, Dibenzo[def,p]chrysene and Three Environmental Mixtures in the FVB/N Mouse.&nbsp; Toxicol. Appl. Pharmacol. 264:377-386. NIHMS 407423</p><br /> <p>*Benninghoff, A.D. and <span style="text-decoration: underline;">Williams, D.E</span>. (2013) The Role of Estrogen Receptor Beta in Transplacental Cancer Prevention by Indole-3-Carbinol.&nbsp; Cancer Prev. Res. 6:339-348.</p><br /> <p>Larkin, A., Siddens, L.K., Krueger, S.K., Tilton, S.C., Waters, K.M., <span style="text-decoration: underline;">Williams, D.E</span>. and Baird, W.M. (2013) Application of a Fuzzy Neural Network Model in Predicting Polycyclic Aromatic Hydrocarbon-Mediated Perturbations of the CYP1B1 Transcriptional Regulatory Network in Mouse Skin.&nbsp; Toxicol. Appl. Pharmacol. 267:192-199. NIHMS 441901</p><br /> <p>Shorey, L.E., Madeen, E.P., Atwell, L.L., Ho, E., L&ouml;hr, C.V., Pereira, C.B., Dashwood, R.H. and <span style="text-decoration: underline;">Williams, D.E</span>. (2013) Differential Modulation of Dibenzo[def,p]chrysene Transplacental Carcinogenesis: Maternal Diets Rich in Indole-3-Carbinol Versus Sulforaphane. Toxicol. Appl. Pharmacol. 270:60-69.</p><br /> <p>Watson, G., Beaver, L., <span style="text-decoration: underline;">Williams, D.,</span> Dashwood, R. and Ho, E. (2013) Phytochemicals from Cruciferous Vegetables, Epigenetics, and Prostate Cancer Prevention. Am. Assoc. Pharmaceut. Sci., DOI: 10:10.1208/s12248-013-9504-4.</p><br /> <p>Kaur, P., Shorey, L., Ho, E., Dashwood, R.H. and <span style="text-decoration: underline;">Williams, D.E.</span> (2013). The Epigenome as a Potential Mediator of Cancer Prevention and Disease Prevention in Prenatal Development.&nbsp;&nbsp; Nutr. Rev. 71:441-457.</p><br /> <p>Crowell, S.R., Sharma, A.K., Amin, S., Soelberg, J.J., Sadler, N.C., Wright, A.T., Baird, W.M., <span style="text-decoration: underline;">Williams, D.E</span>. and Corley, R.A. (2013) Impact of Pregnancy on the Pharmacokinetics of Dibenzo[def,p]chrysene in Mice. Toxicol. Sci. 135:48-62.</p><br /> <p>Liang, J.F., Q. Yang, <span style="text-decoration: underline;">M. J. Zhu</span>, Y. Jin, M. Du. (2013). AMP-activated protein kinase (AMPK) &alpha;2 subunit mediates glycolysis in postmortem skeletal muscle. Meat Science, 95: 536-541</p><br /> <p>Hu, J., B. Wang, X. Fang, W.J. Means, R.J. McCormick, M. Gomelsky, and <span style="text-decoration: underline;">M. J. Zhu</span>. (2013). c-di-GMP signaling regulates E. coli O157:H7 adhesion to colonic epithelium. Veterinary Microbiology, 164: 344-351</p><br /> <p>Yan, X.,Y. Huang, J. X. Zhao, C. J. Rogers, <span style="text-decoration: underline;">M. J. Zhu</span>, S. P. Ford, P. W. Nathanielsz, and M. Du. (2013). Maternal obesity down-regulates microRNA let-7g expression, a possible mechanism for enhanced adipogenesis during ovine fetal skeletal muscle development. International Journal of Obesity, 37: 568-575</p><br /> <p>Harries, S.M., W.F. Yue, S.A. Olsen, J. Hu, W.J. Means, R.J. McCormick, M. Du, and <span style="text-decoration: underline;">M. J. Zhu.</span> (2012). Salt at concentrations relevant to meat processing enhances Shiga toxin 2 production in Escherichia coli O157:H7. International Journal of Food Microbiology, 159:186-192</p><br /> <p>Wang, H., J. Zhao, N. Hu, J. Ren, M. Du, and <span style="text-decoration: underline;">M. J. Zhu</span>. (2012). Side-stream smoking reduces inflammation and increases expression of tight junction proteins in the intestine. World Journal of Gastroenterology, 18: 2180-2187</p><br /> <p>Wang, H., J. Zhao, Y. Huang, X. Yan, A.M. Meyer, M. Du, K. Vonnahme, L.</p><br /> <p>Reynolds, J. Caton and <span style="text-decoration: underline;">M. J. Zhu</span>. (2012). Effects of maternal plane of nutrition and increased dietary selenium in first parity ewe on inflammatory response in the ovine neonatal gut. Journal of Animal Science, 90: 325-333.</p><br /> <p>Yue, W.F., M. Du, and <span style="text-decoration: underline;">M. J. Zhu</span>. (2012). High temperature in combination with UV irradiation enhances horizontal transfer of stx2 gene from E. coli O157:H7 to non- pathogenic E. coli. PLoS One, 7: e31308 (1-7)</p><br /> <p>Huang, Y., A. K. Das, Q. Y. Yang, M. J. Zhu, and M. Du. (2012). Zfp423 promotes adipogenic differentiation of bovine stromal vascular cells. PLoS One, 7: e47496.</p><br /> <p>Das, A. K., Q. Y. Yang, X. Fu, J. F. Liang, M. S. Duarte, <span style="text-decoration: underline;">M. J. Zhu</span>, G. D. Trobridge, and M. Du. (2012). AMP-activated protein kinase stimulates myostatin expression in C2C12 cells. Biochemical and Biophysical Research Communications, 427:36-40.</p><br /> <p>Yan, X., <span style="text-decoration: underline;">M. J. Zhu</span>, M. V. Dodson, and M. Du. (2012). Developmental programming of fetal skeletal muscle and adipose tissue development. Journal of Genomics, 1,29-38.</p><br /> <p>Huang, Y., J. X. Zhao, X. Yan, <span style="text-decoration: underline;">M. J. Zhu</span>, N. M. Long, R. J. McCormick, S. P. Ford, P. W. Nathannielsz, and M. Du. (2012). Maternal obesity enhances collagen accumulation and cross-linking in skeletal muscle of ovine offspring. PLoS One. 7: e31691(1-8).</p>

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Benninghoff, Abby (abby.benninghoff@usu.edu) - Utah State University; Coulombe, Roger (roger@usu.edu) - Utah State University; Harrington, H.Michael (Michael.Harrington@colostate.edu) - Colorado State University; Helferich, Bill (helferic@illinois.edu) - University of Illinois; Nerurkar, Pratibha (Pratibha@hawaii.edu) - University of Hawaii; Ricketts, Marie-Louise (mricketts@cabnr.unr.edu) - University of Nevada Reno; Turner, Nancy (n_turner@tamu.edu) - Texas A&M University; Weir, Tiffany (Tiffany.weir@colostate.edu) - Colorado State University; Williams, David (david.williams@oregonstate.edu) - Oregon State University; Zhu, Meijun (meijun.zhu@wsu.edu) - Washington State University

Brief Summary of Minutes

Accomplishments

Objective 1: Determine the mechanisms by which dietary bioactive compounds protect against human diseases.<br /> <br /> Dr. Abby Benninghoff and colleagues in the Applied Nutrition Research Group (Utah State University) previously developed a new rodent diet that models typical Western nutrition. Rodent cancer studies typically use defined diets with nutrient profiles optimized for rodent health. However, a defined rodent diet that represents typical American nutrition in all aspects, including calorie sources and macro- and micronutrient composition, was not available. They therefore used a nutrient density approach to formulate the new Total Western Diet (TWD) based on NHANES data for macro- and micronutrient intakes. As proof of principle, they employed the azoxymethane (AOM) model of colorectal cancer in mice fed either TWD or AIN93G basal diets supplemented with or without 0.2% green tea extract in the drinking water. Previously, they reported that green tea extract suppressed the development of preneoplastic lesions, termed aberrant crypt foci, in mice fed the TWD, but not in mice fed the optimal AIN93G diet. During the current reporting period, they have performed additional analyses to determine the impact of the experimental diets and green tea extract on the cecal metagenome and short chain fatty acids. They have determined that green tea extract was associated with increased cecum weight and negatively correlated with final body weight. Also, the relative abundance of bifidobacterium species was higher in animals provided green tea and the TWD. A metagenomics analysis of the cecal contents revealed that green tea supplementation reduced the relative abundance of genes associated with butyrate metabolism, suggesting a reduced capacity for butyrate production. Additionally cecal butyrate, acetate and total short chain fatty acids were lower in mice supplemented with green tea. These observations suggest that green tea may reduce body weight gain, without any accompanying change in energy intake, by reducing the amount of energy extracted from the diet by gut microbiota.<br /> Last year, Dr. Benninghoff and colleagues reported results of a second study with the TWD using the AOM+dextran sodium sulfate (DSS) model of inflammation?associated colorectal cancer. From that study, they determined that the effect of TWD on tumorigenesis in mice was attributed to the micronutrient fraction of the diet. In 2014, we performed a third pre?clinical study to investigate the impact of TWD in a genetic model of colorectal cancer using the APCmin/+ mouse model. APCmin/+ mice spontaneously develop tumors of the small intestine, and with the addition of 1% DSS via drinking water, they also develop colon tumors. This experiment employed a 2x3 design, where mice received either 1%DSS or plain water and either the optimal AIN93G diet, the TWD or the 45% fat DIO diet. None of the experimental diets, nor addition of DSS, significantly affected the incidence of small intestine (SI) tumors, although a significant main effect of the DIO diet was evident for SI tumor multiplicity and tumor burden. TWD did not markedly enhance carcinogenesis of the small intestine. Alternatively, the TWD had a profound effect on tumorigenesis in the colon, notably in animals provided 1%DSS to promote colonic inflammation. Exposure to the TWD significantly increased colon tumor incidence and caused a 5?fold increase in colon tumor multiplicity, whereas the DIO diet was without any effect on colon tumorigenesis.<br /> <br /> Dr. Roger Coulombe and colleagues (Utah State University) reported on a project in which they are using probiotics as chemopreventive agents. Probiotic bacteria such as Lactobacillus (the type used in fermented foods such as yogurt) have been shown in laboratory and limited clinical studies, to prevent the absorption and reduce exposure to dietary carcinogens, such as AFB1. The presumed mechanism of action is via non?specific binding of AFB1 by cell wall glycoproteins, which reduces intestinal absorption and hence bioavailability of this mycotoxin. They have previously reported that the probiotic Lactobacillus (a mixture of Lactobacillus rhamnosus strain GG and LC-­705, Propionibacterium freundenreichii sp shermani and Bifidobacterium sp (LGG)) protected against markers of aflatoxicosis in turkeys, one of the most sensitive animals known to AFB toxicity. This year, they used RNA? sequencing (RNA?seq) to investigate the impact of probiotics on the expression pattern of splenic RNA transcripts in turkeys challenged with dietary AFB1. Ten?day old male Nicholas strain domestic turkeys were randomized into one of four groups: LGG only, LGG+AFB1, PBS control, and AFB1 only. Birds were pretreated with probiotic (5 X 10 CFU/0.5 ml PBS) or PBS by oral gavage for the first 10 days, before starting a 10?day dietary AFB1 treatment (1 ppm). RNA?seq libraries were generated from 3 spleen samples per treatment group (n = 12) and were sequenced on the Illumina GA IIx. Over 105 M single?end reads were produced and de novo assembled into approximately 270,000 predicted transcript fragments. 982 transcripts had significant differential expression in at least one pair?wise comparison between treatment groups. AFB1 exposure down-regulated transcripts from antimicrobial genes such as angiogenin and lysozyme G; however, other immune-related transcripts, including granzyme A, lymphotactin, and perforin 1, were up-regulated. Increased expression of these interleukin-2 response genes could be indicative of lymphocyte activation or apoptosis. Probiotic + AFB1 mitigated some expression changes induced by AFB1, but probiotics alone had a suppressive effect on immune transcripts and may affect the cytotoxic potential of turkey splenocytes. Pathways and genes identified by transcriptome analysis in the spleen provide targets to elucidate the molecular basis of AFB1 immunotoxicity and to determine the mechanism of probiotic chemoprevention at the RNA level. One possible interpretation of these results is that probiotics alter the microbiome in the turkey, reducing the population of certain pathogens, thus lowering the levels of “maintenance” immune transcripts normally expressed in the spleen.<br /> <br /> Dr. Pratibha Nerurkar and colleagues (University of Hawaii) have recently demonstrated that bitter melon juice (BMJ) improves not only glucose and lipid metabolism, but also prevents weight gain in mice fed a high-fat-diet (HFD) which contains 58% fat. BMJ was also found to improve chronic systemic and hepatic inflammation. Recent mechanistic studies also indicate a role for adipose and intestinal inflammation in the pathophysiology of obesity and Type 2 Diabetes (T2D). The team’s current data demonstrates that BMJ improves macrophage infiltration and inflammation in adipose tissue and intestinal inflammation in mice fed the HFD. BMJ was found to reduce TNF-a and IL-1b. This resulted in reduced insulin signaling and inhibition of insulin resistance, which is mediated via activation of the inflammasome. Dr Nerurkar tested the impact of BMJ in studies using high-fat diet fed mice, and discovered that BMJ reduces fat content and fasting glucose levels. BMJ reduced macrophage infiltration into adipose tissue, and also reduced TLR4 and NF-kB in circulation. Protein levels for leptin, MCP-2 and TNF-a were also reduced. Expression levels of PGE2 and COX-2 in the gut were reduced to normal levels with BMJ, which may be associated with increases in AMPK1 and reduction in TLR4. Lactobacillales present in the cecum was elevated by BMJ. Future studies are planned to understand how BMJ influences gut microbiota, inflammation and obesity-associated T2D.<br /> <br /> Dr Marie-Louise Ricketts and colleagues (University of Nevada Reno) continued their investigation into the modulation of FXR-target genes in the small intestine and liver by a grape seed procyanidin extract (GSPE), and helped to elucidate a novel molecular mechanism by which GSPE lowers serum triglyceride levels. Their previous studies identified the regulatory effects of GSPE on known intestinal FXR target genes in human colorectal adenocarcinoma (Caco-2) cells, namely apical sodium dependent bile acid transporter (ASBT), ileal bile acid binding protein (IBABP), fibroblast growth factor 15/19 (FGF15/19) and organic solute transporters alpha and beta (OSTa/b. They have now extended these studies in vivo using both C57BL/6 wild type and Farnesoid X receptor (FXR) knockout (FXR-/-) mice. Their results demonstrate that GSPE differentially modulates intestinal FXR-target gene expression in the intestine in an FXR-dependent manner, ultimately resulting in decreased enterohepatic bile acid recirculation. These GSPE-mediated alterations in FXR target-gene expression result in the impairment in intestinal BA up-take into the intestine, transport across the intestine, as well as decreasing the amount of BA that return to the liver via the portal circulation; an observation supported by a significant 46% reduction in serum bile acid levels following GSPE administration in wild type mice. Subsequent studies have also revealed that GSPE causes a significant increase in the mRNA expression of CYP7A1, which results in increased cholesterol 7a-hydroxylase protein expression, and increased conversion of cholesterol into bile acids. The team proposes that the impairment in bile acid absorption caused by GSPE administration may represent another mechanism involved in its’ hypotriglyceridemic effect. <br /> Dr Ricketts and colleagues have also investigated the actions of GSPE in vivo, in the presence of the bile acid binding resin, cholestyramine. They have discovered that GSPE and cholestyramine co-administration can exert beneficial metabolic alterations, including decreased triglyceride levels.<br /> <br /> Dr. Nancy Turner and colleagues (Texas A&M) reported on projects studying the impact of dietary bioactives and other environmental inputs on colon microbiota and how these impact colon and systemic health. She gave an update on the impact of a condensed tannin rich sorghum bran on colon microbiota, plasma metabolites, and microbial metabolites in overweight human subjects. She indicated that metabolites reflective of metabolic syndrome were improved with the sorghum bran intervention and the changes in circulating metabolites of polyphenols were, in part, reflected by changes in the concentration of those molecules in fecal samples. She is also studying the impact of these sorghum polyphenols on serum lipoproteins. She reported on a new study using dried plums, in which the levels of early lesions of colon cancer were reduced by 50% in rats consuming the plum diet. She is sequencing fecal microbial samples and will be studying epigenetic regulation of colon epithelial cell gene expression with samples from this study. She also reported the impact of microgravity and radiation on fecal microbial populations. She will be continuing this work to understand how radiation suppresses apoptosis in colon adult stem cells through epigenetic mechanisms regulated by microbial metabolites.<br /> Inflammatory bowel disease rates are increasing worldwide and we now know that colon inflammation is a major driver of colon cancer, and the interaction between the bacteria present in the colon and the epithelial cells can contribute to the inflammatory state of the tissue. In addition, perturbations in microbiota are thought to be linked to either the risk of obesity or to modify the systemic inflammatory tone in overweight/obese subjects. It may be that the link between obesity and colon cancer occurrence is due to the alterations in microbiota and their metabolism that occurs with obesity. The overall purpose of this project is to understand how the intestinal environment (colon and bacteria) is modified in response to biologically active compounds present in our diet, with the main goal being the identification of compounds that are able to suppress inflammation and colon cancer. A secondary goal is to appreciate how diet intercedes in the microbe-induced physiologic changes that occur in overweight/obese subjects.<br /> They have demonstrated in a recent publication that butyrate not only enhances histone acetylation, but also suppresses global DNA methylation. Through the combination of butyrate’s effects on histone acetylation and promoter methylation, expression of Tnfrsf25 and Dapk1, which are associated with regulation of apoptosis were upregulated in a colon cancer cell line. <br /> The team also demonstrated that polyphenolic molecules in certain varieties of sorghum grain affect the metabolism of microbiota, which leads to changes in fecal concentrations of total short chain fatty acids and butyrate. The changes in microbial metabolism are probably induced by the changes in microbiota detected in feces from rats. Consumption of diets containing brans isolated from black, sumac or high tannin black varieties of sorghum had reduced ratios of Firmicutes to Bacteriodetes. Lower ratios are associated with reductions in both intestinal inflammation and obesity risk in humans. Consumption of the black sorghum bran containing anthocyanidins and the sumac sorghum containing condensed tannins resulted in relatively small increases in injury scores in rats exposed to DSS, an injury model of inflammatory bowel disease. <br /> Overweight subjects consuming a breakfast cereal made from sumac sorghum had elevated circulating levels of microbially derived metabolites of plant phenols and aromatic amino acids. Some of these compounds are found at low concentrations in individuals with impaired glucose tolerance, while others are typically suppressed in individuals suffering from ulcerative colitis. These observations were initially made using untargeted metabolomics with plasma samples. However, some of the metabolites most modified in the plasma have now been confirmed to exist in the fecal samples, suggesting the site of generation was the intestine. The same subjects had changes in fecal microbiota, with a distinct elevation in the proportion of Faecalibacterium prausnitzii, a bacteria associated with reduced inflammatory states. <br /> Some of their newest work has determined that factors, including diet, weightlessness and radiation, which are characteristic of the environment experienced by individuals during space flight, impact the inflammatory state of the colon. In addition, most factors also induce changes in the microbiota, which may be one of the initiating factors in the alterations in the expression of inflammatory mediators occurring in the colon. Importantly, they found circulating levels for many of these same inflammatory mediators were also altered. These observations suggest that some of the pro-inflammatory responses that occur during spaceflight may originate as a result of the impact of these space environmental factors on the intestine.<br /> The last project utilized dried plums to determine whether the impact of this fiber and bioactive compound rich food source would alter colon carcinogenesis. They discovered that including the dried plums in the diet at a level that would correspond to the human equivalent serving size effectively reduced the formation of early pre-neoplastic lesions by 50%. The team are currently in the process of initiating analyses that will determine whether or not the mechanisms involved in the protection are associated with changes in the microbiota and their metabolism.<br /> Observations from these studies indicate that part of the protection against intestinal disease and the improvements in systemic health conferred by biologically active compounds is through their effects on the bacterial populations and the byproducts of their metabolism. Alterations to the colon environment induced by these dietary compounds could regulate transcription of genes involved in protection against colon carcinogenesis through epigenetic mechanisms, including histone acetylation and DNA promoter methylation. The benefits derived from these compounds are not constrained to the colon, but may impact overall health because microbial metabolites of the large polyphenolic molecules are being absorbed into systemic circulation.<br /> <br /> Dr. Tiffany Weir (Colorado State University) reported on her work to develop biological markers to improve assessment of nutrition education programs. The project will use global metabolomic profiling to detect true intake of fruits and vegetables. The overall goal is to identify those biomarkers that not only reflect intake, but that are also associated with health markers (e.g., insulin sensitivity). Stool metabolites obtained from the BENEFIT study were used to segment people into food intake patterns, compared to reported intake patterns. Using the OPLS-DA analytical approach, they were able to discriminate between tertiles of intake. They found that some metabolites were reflective of intake patterns. Currently the team is conducting an intervention study to demonstrate that the biomarkers are indicative of intake in a controlled feeding study. The primary outcome is to validate the OPLS-DA model and to identify other markers present in urine. Secondary measures will include plasma biomarkers (a-hydroxybutyrate) and stool microbiome analysis; additionally, a dried blood spot method is under development as an alternative for plasma collection to measure a-hydroxybutyrate. The team is also conducting other projects to explore the impact of artificial sweeteners, phytoestrogen supplementation, as well as diet and genetic factors on the intestinal microbiome.<br /> <br /> Dr. Dave Williams and his team (Oregon State University) continue to research dietary chemoprevention of cancer, specifically protection of the fetus/infant from transplacental carcinogens by dietary supplementation with plant phytochemicals or the whole foods from which they were derived. The emphasis continues to be on phytochemicals from cruciferous vegetables primarily indole-3-carbinol (I3C) and sulforaphane (SFN). <br /> At the meeting Dr. Williams reported that he is currently trying to understand why a humanized Cyp1B1 mouse model is not responsive to dibenochrysene (DBC) induction of T-cell acute lymphoblastic leukemia (T-ALL). Cyp1B1 is important for adduct formation in the spleen. They found that adducts in fetal lung are present at the same high levels as those found in the maternal lung. Indole-3-carbinol did not affect adduct formation, but Chlorophyllin was able to reduce circulating aflatoxin. They are currently performing a human study to evaluate the pharmacokinetics of benzoalphapyrene (BaP) at the zemptomole level (which is non-hazardous). Other on-going work relates to the evaluation of epigenetic effects on DNA methyltransferases and HDAC (Lys) inhibitors in newborns. I3C causes global DNA methylation levels to return to normal, even in the presence of PAH administration. The team is also evaluating the role of Nrf-2 and effects of maternal dietary SFN in newborns using Nrf-2 KO animals. Initial observations show only a few deaths from T-ALL, but those animals were fed the DBC/SFN diet.<br /> <br /> Dr. Meijun Zhu and colleagues (Washington State University) have been assessing the impact of bioactives on inflammatory bowel disease and gut microbiota. Impairment in gut epithelial barrier function is a key predisposing factor for inflammatory bowel disease, type 1 diabetes (T1D) and related autoimmune diseases. Dr Zhu’s work has shown that a grape seed extract (GSE) decreases intestinal permeability in IL-10 deficient mice. The GSE was associated with elevated intestinal AOX levels and reduced serum TNF-a levels. Dr Zhu is also studying the effects of goji berry, which has high AOX activity, polyphenols and other beneficial compounds. Dr Zhu has used IL-10 KO mice and the DSS-induced colitis model, and has discovered that DSS causes weight-loss in mice fed a control diet, but goji-berry supplementation helped to prevent as great a weight-loss with DSS, compared to control diet. Goji-berry improved disease scores, but there were no changes in AOX or AOX-markers in the colon. Short chain fatty acids (SCFA) were altered by goji-berry; acetate is reduced while butyrate and isovaleric acid are elevated. Butyrate producing bacteria and butyrate gene expression were increased following goji-berry. There were no significant differences in bacterial groups associated with IBD, but Actinobacteria and Bifidobacteria levels were elevated by goji-berry. There was a reduction in IL-17A, INF-a and TGF-b expression with goji-berry. Results suggest the goji-berry improvement in IBD results from changes in bacterial groups.<br /> Dr Zhu has also found that maternal obesity induces impaired glucose tolerance and lower serum insulin levels, inflammation and impaired gut barrier function in female offspring of non-obese diabetic (NOD) mice. Concomitantly, female offspring born to obese dams showed more severe islet lymphocyte infiltration (major manifestation of insulitis) in the pancreas, suggesting enhanced gut permeability in the offspring of obese dams might predispose them to development of T1D. On the other hand, using interleukin-10 (Il10)-deficient mice, they found that 12 weeks of GSE supplementation improved gut barrier function, as indicated by decreased intestinal permeability and increased the colonic goblet cell density and mucin mRNA expression. Immunohistochemical analyses revealed lower ?-catenin accumulation in the crypts of colon tissues of GSE supplemented mice, which was associated with decreased mRNA expression of two down-stream effectors of Wnt/catenin signaling, myelocytomatosis oncogene protein (Myc) and Cyclin D1(ccnd1). Consistently, GSE supplementation decreased the colonic proliferating cell nuclear antigen (PCNA) positive cells, a well-known cell proliferation marker, and weakened extracellular-signal-regulated kinase (ERK1/2) signaling. Data indicate that GSE exerts its beneficial effects in IL-10-deficient mice, probably via inhibiting the Wnt/?-catenin pathway. <br /> <br /> Objective 2: Elucidate mechanisms of action of dietary toxicants and develop biomarkers for human risk assessment and disease prevention. <br /> <br /> Dr. Ron Riley (USDA-ARS-Georgia) have initiated studies have to identify the subcellular localization of sphingoid bases and sphingoid base-1-phosphates in mice that are susceptible or resistant to fumonisin-disruption of sphingolipid metabolism and induction of neural tube defects (NTD). Towards this end, a collaborator at Creighton University developed a mouse embryonic fibroblast cell line (MEFs) from fumonisin susceptible and resistant mouse strains. The results show that the bioactive sphingoid base-1-phosphates (Sa1P) are present at higher concentrations in the nucleus than in the cytoplasm and that the levels are highest in the susceptible strain. The protein target of the elevated nuclear Sa1P appears to be histone deacetylase. This is important because human exposure to the histone deacetylase inhibitor, valproic acid, during pregnancy has been shown to cause NTDs. Accumulation of nuclear Sa1P, coupled with a reduction in histone deacetylase activity therefore represents a plausible mechanism for fumonisin induction of NTDs. <br /> Additional studies were completed which confirm that humans consuming diets containing high levels of fumonisin have significantly higher levels of sphingolipid metabolites (sphinganine 1-phosphate) in their blood when compared to low fumonisin exposure groups. The levels of sphingolipid metabolites in the blood were significantly correlated with fumonisin B1 in the urine. The results are consistent with the hypothesis that dietary intake of high levels of fumonisin contaminated corn results in disruption of sphingolipid metabolism in humans. Disruption of sphingolipid metabolism is the proximate cause of all the animal diseases known to be caused by fumonisin, including neural tube defects in mice. The incidence of neural tube defects is high in countries where corn is a dietary staple and is likely to be contaminated with high levels of fumonisin and aflatoxin. The results of their biomarker-based studies were provided to the Secretary of Food Security and Nutrition (SESAN) in Guatemala and also other government agencies and non-governmental organizations (Catholic Relief Services Guatemala) along with data on both fumonisin and aflatoxin co-occurrence in Guatemalan corn. As a result of this work, a plan of action has been developed by SESAN and others (World Food Programme) to minimize both aflatoxin and fumonisin exposure in Guatemala. The results were also shared with the US Agency for International Development (USAID) and USDA-FAS in Guatemala. These studies were conducted as part of a collaboration between USDA-TMRU (Athens, GA), Centro de Investigaciones en Nutrición y Salud in Guatemala, Creighton University and Duke University.<br /> <br /> Dr. Dave Williams and colleagues (Oregon State University) currently focuses on mechanisms of action and biomarkers associated with an important class (3 of the top 10 ATSDR environmental chemicals of concern), polycyclic aromatic hydrocarbons (PAHs), of food-borne carcinogens. These have included molecular biomarkers such as alterations in levels of tumor suppressor genes, DNA adductions, etc., in addition to biological endpoints.<br /> <br /> Objective 3: Discover and characterize novel dietary compounds that have beneficial or adverse effects on human health. <br /> <br /> Dr. Bill Helferich and colleagues (University of Illinois) have been assessing the long-term effect of exposure to relevant dietary levels of genistein (GEN) on estrogen receptor-positive (ER+) human breast cancer (MCF-7) progression after GEN withdrawal in athymic mice xenograft model. The following in vivo studies were conducted to determine the effect on the growth of MCF-7 tumors: 1) implantation (19 weeks) and withdrawal (6 weeks) of 17b-estradiol (E2); 2) dietary GEN 500 and 750 ppm during treatment/withdrawal for 23/10 and 15/9 weeks, respectively; and, 3) dietary soy protein isolate (SPI) containing GEN 180 ppm 31/9 weeks of treatment/withdrawal. MCF-7 tumors grew fast in the presence of E2 implantation and abruptly regressed completely after E2 withdrawal. At different rates, dietary GEN alone (500 and 750 ppm) and GEN (180 ppm)-containing SPI stimulated MCF-7 tumor growth. After removal of the stimulus diet, tumors induced by 750 ppm GEN, but not 500 ppm GEN or SPI, regressed completely. The protein expression of epidermal growth factor receptor 2 (HER2) was higher in the GEN- and SPI-induced non-regressing (GINR) tumors compared to MCF-7 and E2 controls. In conclusion, long-term consumption of low GEN doses (?500 ppm) promotes MCF-7 tumor growth and elicits changes resulting in GINR tumors with more aggressive and advanced growth phenotypes. <br /> <br /> Dr. Marie-Louise Ricketts and colleagues (University of Nevada Reno) have been fractionating the whole GSPE extract to separate out the monomeric, dimeric and trimeric fractions to facilitate examination of which fraction or fractions are responsible for the enhanced transactivation of FXR observed in the presence of the bile acid, CDCA, and GSPE. To date they have isolated both the monomeric and dimeric fractions and have performed TLC analysis of the fractions isolated and have begun HPLC analysis of the monomeric fraction. Once they have performed a more detailed analysis of the fractions isolated they will test the ability of the fractions to transactivate FXR in in vitro transient transfection studies.<br /> <br /> Objective 4: Increase beneficial or decrease adverse effects of bioactive constituents and microbes in food. <br /> <br /> Dr. Mendel Friedman and colleagues (USDA-California) discovered that antimicrobial wine marinades behave as broad-spectrum antibiotics against four pathogens, suggesting that they have the potential to be used as food preservatives. The researchers also found that edible antimicrobial films incorporated with carvacrol and cinnamaldehyde inactivated Salmonella Newport on organic leafy greens in closed plastic bags, suggesting that the films have the potential for large-scale use against contaminated leafy greens. They also found that a recently developed commercially available rice hull smoke extract protected mice against endotoxemia, a virulent disease that results mainly from infection by Gram-negative bacteria, suggesting its value as a replacement in food for widely used wood-derived smokes. Additional collaborative studies found that a polysaccharide isolated from the liquid culture of Lentinus edodes (Shiitake) mushroom mycelia containing black rice bran also protected mice against a Salmonella lipopolysaccharide-induced endotoxemia. The USDA research team also discovered that heating of milk spiked with Shiga toxin 2 (Stx2) in a microwave oven at 198 kJ reduced the Stx2 activity, suggesting that microwaving of contaminated food might inactivate the toxin produced by E. coli. The team also found that the interactions of five antimicrobial compounds with monolayers of bacterial phospholipids depended on both the structure of the antimicrobials and the composition of the monolayers, providing insight into the mechanism of the molecular interactions between naturally-occurring antimicrobial compounds and the phospholipids of the bacterial cell membrane that govern activities.<br /> The amino acids L-cysteine protected frog embryos against adverse effect of two toxins present in processed food, acrylamide and furan, suggesting that the protective effect of the amino acid merits evaluation in humans. Also during the current reporting period, the tomato glycoalkaloid tomatine reduced the size of transplanted colon tumors in mice by38% after two weeks compared to control, suggesting that the glycoalkaloid may help prevent colon cancer.<br /> <br /> Dr. Dave Williams (Oregon State University): A major effort this past year has been focused on reducing human health risks from food-borne pathogens and environmental contaminants. I3C is especially potent in reducing the risk to the fetus from exposure in utero to chemical carcinogens ingested in food. <br />

Publications

Benninghoff, A.D. and Williams, D.E. (2013) The role of estrogen receptor beta (ER?) in transplacental cancer prevention by indole-3?carbinol. Cancer Prevention Research 6(4): 339?348.<br /> <br /> Polejaeva, I., Broek, D., Walker, S., Zhou, W., Walton, M., Benninghoff, A.D., Faber, D. (2013) Longitudinal study of reproductive performance of female cattle produced by somatic cell nuclear transfer. PLoS ONE 8(12): e84283.<br /> <br /> Hintze, K.J, Cox, J.E., Rompato, G., Benninghoff, A.D., Ward, R.E., Broadbent, J., and Lefevre, M. (2014) Broad scope method for creating humanized animal models for animal health and disease research through antibiotic treatment and human fecal transfer. Gut Microbes 5(2): 1-9.<br /> <br /> Tang X, Kuhlenschmidt TB, Li Q, Ali S, Lezmi S, Chen H, Pires-Alves M, Laegreid WW, Saif TA, Kuhlenschmidt MS. (2014) A mechanically-induced colon cancer cell population shows increased metastatic potential. Mol Cancer. 13(1):131. <br /> <br /> Monson, M. S., Settlage, R.E., McMahon, K.W., Mendoza, K.M., Rawal, S., El Nezami, H., Coulombe, R.A., and K.M. Reed. (2014) Response of the Hepatic Transcriptome to Aflatoxin B1 in Domestic Turkey. PLOS One 9(6): doi: 10.1371/journal.pone.0100930.<br /> <br /> Rawal, S., Bauer, M. M., Mendoza, K.M., El?Nezami, H., Hall, J.O., Kim, J?E., Stevens, J.R., Reed, K.M., and R.A. Coulombe (2014). Aflatoxicosis Chemoprevention by Probiotic Lactobacillus and its Impact on BG Genes of the Major Histocompatibility Complex. Research in Veterinary Science. pii: S0034?5288(14)00170?2. doi: 10.1016/j.rvsc.2014.06.008.<br /> <br /> Kim, J.E., Bunderson, B., Croasdell, A., Reed, K.M, and R.A. Coulombe, Jr. (2013) Alpha?class glutathione S? transferases in Wild Turkeys: Characterization and Role in Resistance to the Carcinogenic Mycotoxin Aflatoxin B1. PLOS One 8(4): e60662. doi:10.1371/journal.pone.0060662<br /> <br /> Bunderson, B., Kim, J.E., Croasdell, A., Mendoza, K, Reed, K.M, and R.A. Coulombe, Jr. (2013) Heterologous Expression and Functional Characterization of Avian Mu?Class Glutathione S?Transferases. Comp. Biochem. Physiol. C – Toxicol Pharmacol. 158: 109?116. DOI: 10.1016/j.cbpc.2013.05.007.<br /> <br /> Wu, Y., McEwen, G.D., Tang, M., Yu, T., Dimmick, Zhou, A., Gilbertson, T.A., Coulombe, Jr., R.A., and J.R. Stevens. (2013) Sensing Biophysical Alterations of Human Lung Cells (A549) in the Context of Toxicity Effects of Diesel Exhaust Particles. Cell Biochem Biophys 67(3):1147?56. doi: 10.1007/s12013?013?9618?4.<br /> <br /> Anwar-Mohamed, A., Elshenawy, O.H., Soshilov, A.A., Denison, M.S., Le, X.C., Klotz, L.-O., El-Kadi, A.O.S. (2013) Methylated pentavalent arsenic metabolites are bifunctional inducers as they induce cytochrome P4501A1 (CYP1A1) and NAD(P)H:quinone oxidoreducatase (NQO1) through AhR and Nrf2 dependent mechanisms, Free Radical Biol. Med. 67C, 171-187. PMID: 24161444<br /> <br /> Magiatis, P., Pappas, P., Gaitanis, G., Mexia, N., Melliou, E., Galanou, M., Vlachos, C., Stathopoulou, K., Skaltsounis, A.L., Marselos, M., Velegraki, A., Denison, M.S. and Bassukas, I.D. (2013) Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin, J. Invest. Dermatol. 133, 2023-2030. PMC3714356<br /> <br /> DeGroot, D.E., Hayashi, A. and Denison, M.S. (2014) Lack of ligand-selective binding of the aryl hydrocarbon receptor to putative DNA binding sites regulating expression of Bax and Paraoxonase 1 genes, Arch. Biochem. Biophys. 541, 13-20. PMC3875388<br /> <br /> Addeck, A., Croes, K., Van Langenhove, K., Denison, M.S., Elhamalawy, A., Elskens, M. and Baeyens, W. (2014) Time-integrated monitoring of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in urban and industrial wastewaters using a ceramic toximeter and the CALUX bioassay, Chemosphere 94, 27-35. PMID: 24075528<br /> <br /> Addeck, A., Croes, K., Van Langenhove, K., Denison, M.S., Afify, A.S., Gao, Y., Elskens, M. and Baeyens, W. (2014) Time-integrated monitoring of dioxin-like polychlorinated biphenyls (dl-PCBs) in aquatic environments using the ceramic toximeter and the CALUX bioassay. Talanta 120, 413-418. PMID: 24468390<br /> <br /> Vogel, C.F.A., Khan, E.M., Chang, W.L.W., Wu, D., Haarmann-Stemmann, T., Hoffmann, A. and Denison, M.S. (2014) Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a Role for NF-?B, J. Biol. Chem. 289, 1866-1875. PMC3894361<br /> <br /> Soshilov, A.A. and Denison, M.S. (2013) Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site directed mutagenesis, Molec. Cell. Biol. 34, 1707-1719. PMC3993610<br /> <br /> Bessede, A., Gargaro, M., Pallotta, M.T., Matino, D., Servillo, G., Brunacci, C., Bicciato, S., Mazza, E.M.C., Macchiarulo, A., Vacca, C., Iannitti, R., Tissi, L., Volpi, C., Belladonna, M.L., Orabona, C., Bianchi, R., Lanz, T., Platten, M., Della Fazia, M.A., Piobbico, D., Zelante, T., Funakoshi, H., Nakamura, T., Gilot, D., Denison, M.S., Guillemin, G.J., DuHadaway, J.D., Prendergast, G.C., Metz, R., Geffard, M., Boon, L., Pirro, M., Iorio, A., Veyret, A., Romani, Grohmann, U., Fallarino, F. and Puccetti, P. (2014) Aryl hydrocarbon receptor control of a disease tolerance defense pathway, Nature 511, 184-190. PMC4098076<br /> <br /> Ghorbanzadeh, M., van Ede, K.I., Larsson, M.N., van Duursen, M.B.M., Poellinger, L., Lucke, S., Machala, M., Pencikova, K., Vondracek, J., van den Berg, M., Denison, M.S., Ringsted, T. and Andersson, P.L. (2014) In vitro and in silico derived relative effect potencies of Ah-receptor mediated effects by PCDD/Fs and PCBs in rat, mouse and guinea pig CALUX cell lines, Chem. Res. Toxicol. 27, 1120-1132. PMID: 24901989<br /> <br /> Novotna, A., Korhonova, M., Bartonkova, I., Soshilov, A.A., Denison, M.S., Kolar, M. and Dvorak, Z. (2014) Enantiospecific effects of ketoconazole on aryl hydrocarbon receptor, PLoS One 9(7) e101832. PMC4084896<br /> <br /> Choi, S. H.; Kim, D.-S.; Kozukue, N.; Kim, H.-J.; Nishitani, Y.; Mizuno, M.; Levin, C. E.; Friedman, M., Protein, free amino acid, phenolic, ?-carotene, and lycopene content, and antioxidative and cancer cell inhibitory effects of 12 greenhouse-grown commercial cherry tomato varieties. J. Food Compos. Anal. 2014, 34, 115-127.<br /> <br /> Friedman, M., Rice brans, rice bran oils, and rice hulls: composition, food and industrial uses, and bioactivities in humans, animals, and cells. J. Agric. Food Chem. 2013, 61, 10626–10641, ARIS no. 297371.<br /> <br /> Friedman, M., Antibacterial, antiviral, and antifungal properties of wines and winery byproducts in relation to their flavonoid content. J. Agric. Food Chem. 2014, 62, 6025-6042.<br /> <br /> Friedman, M., The chemistry and multi-beneficial bioactivities of carvacrol (4-isopropyl-2-methylphenol), a component of essential oils produced by aromatic plants and spices. J. Agric. Food Chem. 2014.<br /> <br /> Kim, S. P.; Nam, S. H.; Friedman, M., Rice hull smoke extract protects mice against a Salmonella lipopolysaccharide-induced endotoxemia. J. Agric. Food Chem. 2014, 62, 7753-9.<br /> <br /> Kim, S. P.; Park, S. O.; Lee, S. J.; Nam, S. H.; Friedman, M., A polysaccharide isolated from the liquid culture of Lentinus edodes (Shiitake) mushroom mycelia containing black rice bran protects mice against a Salmonella lipopolysaccharide-induced endotoxemia. J. Agric. Food Chem. 2013, 61, 10987-94.<br /> <br /> Kim, S. P.; Park, S. O.; Lee, S. J.; Nam, S. H.; Friedman, M., A polysaccharide isolated from the liquid culture of Lentinus edodes (Shiitake) mushroom mycelia containing black rice bran protects mice against salmonellosis through up-regulation of the Th1 immune reaction. J. Agric. Food Chem. 2014, 62, 2384-91.<br /> <br /> Nowotarska, S. W.; Nowotarski, K. I.; Friedman, M.; Situ, C., Effect of structure on the interactions between five natural antimicrobial compounds and phospholipids of bacterial cell membrane on model monolayers. Molecules 2014, 19, 7497-7515.<br /> <br /> Rasooly, R.; Hernlem, B.; He, X.; Friedman, M., Microwave heating inactivates Shiga Toxin (Stx2) in reconstituted fat-free milk and adversely affects the nutritional value of cell culture medium. J. Agric. Food Chem. 2014, 62, 3301-3305.<br /> <br /> Williams, J. R.; Rayburn, J. R.; Cline, G. R.; Sauterer, R.; Friedman, M., The potential protective effect of L-cysteine against the toxicity of acrylamide and furan in exposed Xenopus laevis embryos: an interaction study. J. Agric. Food Chem. 2014, 62, 7927-38.<br /> <br /> Zhu, L.; Olsen, C.; McHugh, T.; Friedman, M.; Jaroni, D.; Ravishankar, S., Apple, carrot, and hibiscus edible films containing the plant antimicrobials carvacrol and cinnamaldehyde inactivate Salmonella Newport on organic leafy greens in sealed plastic bags. J. Food Sci. 2014, 79, M61-M66.<br /> <br /> Walsh, H., J.J. Cheng, M.R. Guo. 2014 Effects of carbonation on probiotic survivability, physicochemical and sensory Properties of milk-based symbiotic beverages. J. Food Sci. M604-613.<br /> <br /> Aumsuwan P, Khan SI, Khan IA, Avula B, Walker LA, Helferich WG, Katzenellenbogen BS, Dasmahapatra AK. Evaluation of wild yam (Dioscorea villosa) root extract as a potential epigenetic agent in breast cancer cells. In vitro Cell Dev Biol Anim. 2014 Aug 23 [Epub ahead of print] PMID: 25148825<br /> <br /> Andrade, J.A., Lopez Cintron, J.R., Engeseth, J.J., Helferich, W.G. (2014). Development of a Point-of-Use Fortification Technology for Delivery of Micronutrients in Honduras. J Sci Food Agri. 2014 May 9. doi: 10.1002/jsfa.6736. [Epub ahead of print] PMID: 24817038.<br /> <br /> Andrade, J., Ju, Y.H., Baker, C., Doerge, D.R. and Helferich, W.G. (2014). Long-term exposure to dietary sources of genistein induces estrogen-independence in the human breast cancer (MCF-7) xenograft model. Mol Nutr Food Res. 2014 Feb 24. doi: 10.1002/mnfr.201300780. [Epub ahead of print]. PMID: 24668689<br /> <br /> Strakovsky, R.S., Lezmi, S., Flaws, J.A., Schantz, S.L., Pan, Y.X., Helferich, W.G. (2014). Genistein Exposure During the Early Postnatal Period Favors the Development of Obesity in Female, But Not Male Rats. Toxicol Sci. 2014 138:161-174. PMID: 24361872<br /> <br /> Neese SL, Pisani SL, Doerge DR, Helferich WG, Sepehr E, Chittiboyina AG, Rottee SCK, Smillie TJ, Khan IA (2013) The effects of dietary treatment with S-equol on learning and memory processes in middle-aged ovariectomized rats. Neurotoxicol Teratol 2013 Dec 22. pii: S0892-0362(13)00226-2. doi: 10.1016/j.ntt.2013.12.004. [Epub ahead of print] PMID: 24368316<br /> <br /> Jiang, Y., Gong, P., Madak-Erdogan, Z., Martin, T., Jeyakumar, M., Carlson, K., Khan, I., Smillie, T.J., Chittiboyina, A.G., Rotte, S.C.K., Helferich, W.G., Katzenellenbogen, J.A. and Katzenellenbogen, B.S. (2013). Mechanisms Enforcing the Estrogen Receptor ?-Selectivity of Botanical Estrogens. FASEB J. 27(11): 4406-4418. PMID: 23882126 PMCID:PMC3804744<br /> <br /> Xing, H., Tang, L., Yang, X., Hwang, K., Wang, W., Yin, Q., Wong, N.Y., Dobrucki, L.W., Yasui, N., Katzenellenbogen, J.A., Helferich, W. Cheng, J., Lu, Y. (2013). Selective Delivery of an Anticancer Drug with Aptamer-Functionalized Liposomes to Breast Cancer Cells in Vitro and in Vivo. J Mater Chem B Mater Biol Med. 1(39):5288-5297. PMID: 24159374<br /> <br /> Yang, X., Belosay A., Hartman, J.A., Song H., Doerge D.R. and Helferich W.G. (2013). Estradiol increases ER-negative breast cancer metastasis in an experimental model. 2013. Clin Exp Metastasis. 30(6):711-721. PMID: 24096710<br /> <br /> Sternberg RA, Pondenis HC, Yang X, Mitchell MA, O'Brien RT, Garrett LD, Helferich WG, Hoffmann WE, Fan TM. (2013). Association between Absolute Tumor Burden and Serum Bone-Specific Alkaline Phosphatase in Canine Appendicular Osteosarcoma. J Vet Intern Med. 27(4):955-963. PMID: 23734720<br /> <br /> Turner, R.T., Iwaniec, U.T., Andrade, J., Branscum, A.J., Neese, S.L., Olson, D.A., Wagner, L., Wang, V.C., Schantz, S.L., Helferich, W.G. (2013). Genistein Administered as a Once-Daily Oral Supplement Had No Beneficial Effect on the Tibia in Rat Models for Postmenopausal Bone Loss. Menopause. 20(6):677-686. PMID: 23385720<br /> <br /> Medina-Cleghorn D, Nomura DK. (2014) Exploring metabolic pathways and regulation through functional chemoproteomic and metabolomic platforms. Chemistry & Biology 21, 1171-1184. PMID: 25237861.<br /> <br /> Cai X, Perttula K, Pajouh SK, Hubbard A, Nomura DK, Rappaport SM. (2014) Untargeted lipidomic profiling of human plasma reveals differences due to race, gender, and smoking status. Metabolomics: Open Access 4, 1000131. <br /> <br /> Mulvihill MM, Nomura DK. (2014) Metabolomic Strategies to Map Functions of Metabolic Pathways. AJP Metabolism and Endocrinology 307, E237-E244. PMID: 24918200<br /> <br /> Latimer LN, Lee MR, Medina-Cleghorn D, Kohnz RA, Nomura DK, Dueber JE. (2014) Employing a combinatorial expression approach to characterize xylose utilization in Saccharomyces cerevisiae. Metabolic Engineering 25, 20-29. PMID: 24930894.<br /> <br /> Mulvihill MM, Benjamin DI, LeScolan E, Ji X, Shieh A, Green M, Narasimhalu T, Morris PJ, Luo K, Nomura DK. (2014) Metabolic Profiling Reveals PAFAH1B3 as a critical driver of breast cancer pathogenicity. Chemistry & Biology 21, 831-840. PMID: 24954006<br /> <br /> Benjamin DI, Louie S, Mulvihill MM, Kohnz RA, Li DS, Chan LG, Sorrentino A, Bandhyopadhyay S, Cozzo A, Ohiri A, Goga A, Ng-SW, Nomura DK. (2014) INPP1 Promotes Cancer Aggressiveness by Linking Inositol Phosphate Recycling to Glycolytic and Lipid Metabolism. ACS Chemical Biology 20, 1340-1350. PMID: 24738946<br /> <br /> Kohnz RK, Nomura DK. (2014) Chemical approaches to therapeutically target the metabolism and signaling of the endocannabinoid 2-AG and eicosanoids. Chemical Society Reviews 43, 6859-6869. PMID: 24676249<br /> <br /> Morris PJ*, Medina-Cleghorn D*, Heslin A, King S, Orr J, Krauss RM, Nomura DK. (2014) Organophosphorus flame retardants inhibit specific liver carboxylesterases and cause serum hypertriglyceridemia. ACS Chemical Biology 9, 1097-1103. (*authors contributed equally to the work) PMID: 24597639<br /> <br /> Hunerdosse D, Nomura DK. (2014) Activity-based proteomic and metabolomic approaches for understanding metabolism. Current Opinion in Biotechnology 28C, 116-126. PMID 24594637<br /> <br /> Poole D, Lee M, Tso P, Bunnett N, Yo S, Lieu T, Shiu A, Wang J-C, Nomura DK, and Aponte GW. (2014) Feeding dependent activation of enteric cells and sensory neurons by lymphatic fluid: evidence for a neurolymphocrine system. AJP-Gastrointestinal and Liver Physiology 306, G686-G698. PMID: 24578341<br /> <br /> Dominguez E, Galmozzi A, Chang JW, Hsu K-L, Pawlak J, Li W, Godio C, Thomas J, Partida D, Niessen S, O’Brien PE, Russell AP, Watt MJ, Nomura DK, Cravatt BF, Saez E. (2014) Integrated phenotypic screening and activity-based proteomics defines a role for carboxylesterase 3 in obesity and diabetes. Nature Chemical Biology 10, 113-121. PMID: 24362705<br /> <br /> Medina-Cleghorn D, Heslin A, Morris PJ, Mulvihill MM, Nomura DK. (2014) Multidimensional profiling platforms reveal metabolic dysregulation caused by organophosphorus pesticides. ACS Chemical Biology 9, 423-432. PMID: 24205821<br /> <br /> Nomura DK, Cravatt BF. (2013) Lipid Metabolism in Cancer. Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids 1831, 1497-1498. PMID: 23921253<br /> <br /> Benjamin DI, Cozzo A, Ji X, Roberts LS, Louie SM, Luo K, Nomura DK. (2013) The ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids that fuel cancer pathogenicity. Proceedings of the National Academy of Sciences, USA 110, 14912-14917. PMID: 23980144<br /> <br /> Louie SM*, Roberts LS*, Mulvihill MM, Luo K, Nomura DK. (2013) Cancer cells incorporate and remodel exogenous fatty acids into structural and oncogenic signaling lipids. Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids 1831, 1566-1572. PMID: 23872477 (* authors contributed equally to the work)<br /> <br /> Louie SM, Roberts LS, Nomura DK. (2013) Mechanisms linking obesity and cancer. Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids 1831, 1499-1508. PMID: 23470257<br /> <br /> Medina-Cleghorn D, Nomura DK. (2013) Chemical Approaches to Study Metabolic Networks. Pflugers Archive 465,427-440. PMID: 23296751<br /> <br /> Cao Z, Mulvihill MM, Mukhopadhyay P, Xu H, Erdelyi K, Hao E, Holovac E, Hasko G, Cravatt BF, <br /> <br /> Nomura DK#, Pal Pacher#. (2013) Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice. Gastroenterology 144, 808-817. PMID: 23295443 (# co-corresponding authors)<br /> <br /> Mulvihill MM, Nomura DK. (2013) Therapeutic Potential of Monoacylglycerol Lipase Inhibitors. Life Sciences 92, 492-497. PMID: 23142242<br /> <br /> Kumar M, Roe K, Nerurkar PV, Orillo B, Thompson KS, Verma S and Nerurkar VR. Reduced immune cell infiltration and increased pro-inflammatory mediators in the brain of Type 2 diabetic mouse model infected with West Nile virus. J Neuroinflammation. 2014 11:80. PMID: 24750819<br /> <br /> Rajamoorthi A, Shrivastava S, Steele R, Nerurkar P, Gonzalez JG, Crawford S, Varvares M, Ray RB. Bitter melon reduces head and neck squamous cell carcinoma growth by targeting c-Met signaling. PLoS One. 2013 8(10):e78006. PMID: 24750819 <br /> <br /> Rensvold JW, Ong SE, Jeevananthan A, Carr SA, Mootha VK and Pagliarini DJ. Complementary RNA and Protein Profiling Identifies Iron as a Key Regulator of Mitochondrial Biogenesis. Cell Reports, 2013, 3(1): 237-245 <br /> <br /> Baldwin TT, Zitomer NC, Mitchell TR, Zimeri A-M, Bacon CW, Riley RT and Glenn AE. Seedling blight of maize by Fusarium verticillioides causes accumulation of fumonisin B1 in upper leaves apart from colonization of the leaves. Journal of Agricultural and Food Chemistry, 62: 2118-2125, 2014.<br /> <br /> Riley RT. Naturally Occurring Chemical Carcinogens. In: World Cancer Report 2014, pp. 206-219, B. Stewart and C.P. Wild, eds., International Agency for Research on Cancer, Lyon, France, 2014.<br /> <br /> Torres O, Matute J, Gelineau-van Waes J, Maddox JR, Gregory SG, Ashley-Koch AE, Showker JL, Voss KA, and Riley RT. Human health implications from co-exposure to aflatoxins and fumonisins in maize-based foods in the Latin America: Guatemala a case study. World Mycotoxin Journal DOI 10.3920/WMJ2014.1736. <br /> <br /> Torres O, Matute J, Gelineau-van Waes J,. Maddox JR,. Gregory SG,. Ashley-Koch AE, Showker JL, Zitomer NC, Voss KA, Riley RT. Urinary fumonisin B1 and estimated fumonisin intake in women from high and low exposure communities in Guatemala. Mol. Nutr. Food Res. 58:973-983, 2014. <br /> <br /> Voss KA and Riley RT. Fumonisin toxicity and mechanism of action: overview and current perspectives. Food Safety (Japan) 1:49-69, 2013. <br /> <br /> Voss KA, Riley RT, Gelineau-van Waes J. Fumonisin ¬B1-induced neural tube defects were not increased in LM/Bc mice fed folate deficient diets. Mol. Nutr. Food Res.58:1190-1198, 2014.<br /> <br /> Cho, Y., N.D. Turner, L.A. Davidson, R.S. Chapkin, R.J. Carroll, and J.R. Lupton. 2014. Colon cancer cell apoptosis is induced by combined exposure to the n-3 fatty acid DHA and butyrate through promoter methylation. Experimental Biology and Medicine 239:302-310. PMID: 24495951.<br /> <br /> Morgan, J.L.L., L.E. Ritchie, B.E. Crucian, C. Theriot, H. Wu, S.M. Smith, N.D. Turner, and S.R. Zwart. 2014. Increased dietary iron and radiation in rats promotes oxidative stress, localized and systemic immune system responses, and alters colon mucosal environment. FASEB Journal 28:1486-1498. PMID: 24334706<br /> <br /> Wang, R., Löhr, C.V., Fischer, K., Dashwood, W.M., Greenwood, J.A., Ho, E., Williams, D.E., Ashktorab, H., Dashwood, M.R. and Dashwood, R.H. (2013) Epigenetic Inactivation of Endothelin-2 and Endothelin-3 in Colon Cancer. Internatl. J. Cancer 132:1004-1012. <br /> <br /> Rajendran, P., Kidane, A.I., Yu, T.-W., Dashwood, W.-M., Bisson, W.H., Löhr, C.V., Ho, E., Williams, D.E. and Dashwood, R.H. (2013) HDAC Turnover, CtIP Acetylation and Dysregulated DNA Damage in Colon Cancer Cells Treated With Sulforaphane and Related Dietary Isothiocyanates. Epigenetics 8:612-623. <br /> <br /> Wong, C.P., Hsu, A., Buchanan, A., Palomera-Sanchez, Z., Beaver, L.M., Houseman, E.A., Williams, D.E., Dashwood, R.H. and Ho, E. (2014) Effects of Sulforaphane and 3,3'-Diindolylmethane on Genome-Wide Promoter Methylation in Normal Prostate Epithelial Cells and Prostate Cancer Cells. PLoS One 9:e86787. <br /> <br /> Crowell, S.R., Hanson-Dury, S., Williams, D.E. and Corley, R.A. (2014) In Vitro Metabolism of Benzo[a]pyrene and Dibenzo[def,p]chrysene in Rodent and Human Hepatic Microsomes. Toxicol. Lett. 228:48-55.<br /> <br /> Beaver, L.M., Buchanan, A., Sokolowski, E.I., Riscoe, A.N., Wong, C.P., Chang, J.H., Löhr, C.V., Williams, D.E., Dashwood, R.H. and Ho, E. (2014) Transcriptome Analysis Reveals a Dynamic and Differential Transcriptional Response to Sulforaphane in Normal and Prostate Cancer Cells and Suggests a Role for Sp1 in Chemoprevention. Molec. Nutr. Food Res. Doi: 10.1002/mnfr.2014002689<br /> <br /> Yang, G., H. Wang, Y. Kang, and M. J. Zhu. (2014). Grape seed extract improves epithelial structure and suppresses inflammation in the ileum of Il10-deficient Mice. Food and Function, 5: 2558-2563 <br /> <br /> Wang, B., G. Yang, X. Liang, M. J. Zhu, and M. Du. (2014). Grape seed extract prevents skeletal muscle wasting in Interleukin 10 knockout mice. BMC Complementary and Alternative Medicine, 14:162-169. <br /> <br /> Zhang, H., Y. Xue, H. Wang, Y. Huang, M. Du, and M. J. Zhu. (2014). Mast cell deficiency induces inflammation and exacerbates inflammatory bowel symptoms in Il10-deficiency mice. World Journal of Gastroenterology, 20:9106-9115 <br /> <br /> Wang, H., Y. Xue, B. Wang, J. Zhao, X. Yan, Y. Huang, M. Du, and M. J. Zhu. (2014). Maternal obesity exacerbates insulitis and type I diabetes in NOD mice. Reproduction, 148:73-79. <br /> <br /> Xue, Y., H. Wang, M. Du, and M. J. Zhu. (2014). Maternal obesity induces gut inflammation and impairs gut epithelial barrier function in NOD mice. Journal of Nutritional Biochemistry, 25: 758-764. <br /> <br /> Xue, Y., H. Zhang, H. Wang, J. Hu, M. Du, and M. J. Zhu. (2014). Host inflammatory response inhibits Escherichia coli O157:H7 adhesion to gut epithelium through augmenting mucin expression. Infection and Immunity, 82:1921-1930. <br /> <br /> Zhu, M. J., M. Du, and S.P. Ford. (2014). Impacts of maternal obesity on placental and gut inflammation and health. An invited review. Journal of Animal Science, 92:1840-1849. <br /> <br /> Kandadi, M. R., Y. Hua, M. J. Zhu, S. Turdi, P.W. Nathanielsz, S. P. Ford, and S. Nair. (2013). Influence of gestational overfeeding and obesity on myocardial pro-inflammatory mediators in fetal sheep heart. Journal of Nutritional Biochemistry, 24:1982-1990 <br /> <br /> Wang, H., Y. Xue, H. Zhang, Y. Huang, G Yang, M. Du, and M. J. Zhu. (2013). Dietary grape seed extract ameliorates symptoms of inflammatory bowel disease in interleukin-10 deficient mice. Molecular Nutrition & Food Research, 57:2253-2257. <br /> <br /> Yang, Q. Y., J .F. Liang, C. J. Rogers, J. X. Zhao, M. J. Zhu, and M. Du. (2013). Maternal obesity induces epigenetic modifications to facilitate Zfp423 expression and enhance adipogenic differentiation in fetal mice. Diabetes, 62:3727-3735. <br />

Impact Statements

1. W3122 researchers are identifying new bioactive and potentially cancer-protective strategies to reduce cancer through dietary means. Researchers conducted a follow-up trial to determine the mechanism by which Lactobacillus protects against aflatoxicosis in turkeys. Probiotic Lactobacillus represents a safe and practical cancer chemopreventive strategy, with potential widespread consumer acceptance. Research exploring the mechanisms of protection in a susceptible animal model is an important proof-of-concept toward development for the food industry. For additional information contact Roger Coulombe (roger@usu.edu)
2. W3122 researchers have developed a new rodent diet formulation that models typical US human nutrition and demonstrated its tumor?promoting effects in three different models of colorectal cancer. The TWD is a useful approach to model typical human nutrition in pre-clinical cancer prevention studies designed to identify effective functional foods or dietary supplements. For additional information contact Abby Benninghoff (abby.benninghoff@usu.edu)
3. W3122 researchers have continued the development, validation and application of recombinant cell lines for the detection of endocrine disrupting chemicals and have used these bioassays and other in vitro AhR-based bioassays to identify and characterize a number of novel natural and synthetic chemicals that can activate the AhR signaling pathway. For further information contact Mike Denison (msdenison@ucdavis.edu).
4. W3122 researchers are looking at unique whole food, food component and phytochemical profiles to reduce food-borne pathogen loads and improve health. For additional information contact Mendel Friedman (Mendel.Friedman@ARS.USDA.GOV)
5. W3122 researchers have identified bitter melon juice as a culturally appropriate dietary intervention to control breast cancer and T2D among ethnic minorities in Hawaii. For more information contact Pratibha Nerurkar (Pratibha@hawaii.edu).
6. W3122 researchers are unraveling the complexities underlying the molecular actions of bioactive dietary components by providing evidence of a new molecular mechanism contributing to the triglyceride-lowering ability of a grape seed procyanidin extract. For more information contact Marie-Louise Ricketts (mricketts@cabnr.unr.edu)
7. W3122 researchers are looking for new ways to combat iron deficiency by examining molecular mechanisms that regulate mitochondrial biogenesis during iron deprivation. Moreover, elucidating mechanisms of mitochondrial alteration may provide valuable insight into disease pathogenesis, as mitochondrial dysfunction occurs in diabetes, cancer, and age-related disorders. For more information contact Dave Pagliarini (Pagliarini@wisc.edu)
8. W3122 have shown that the results of the human biomarker studies provide a basis for the design of mechanism-based biomarker studies in areas where consumption of maize contaminated with fumonisin is suspected to contribute to human disease. Preliminary case-control studies are in progress in collaboration with CIENSA, the Government of Guatemala and the Centers for Disease Control (US) to assess the possibility that fumonisin exposure is a contributing factor in human birth defects in Guatemala. For more information contact Ron Riley (ron.riley@ars.usda.gov)
9. W3122 researchers have demonstrated that butyrate influences histone acetylation and DNA promoter methylation, and through these effects is capable of altering expression of key genes involved in regulating colonocyte physiology. They have also shown that polyphenolic molecules derived from certain varieties of sorghum grain can influence colonic microbiota and metabolism during chronic bouts of inflammatory bowel disease, and by so doing, they reduce the increase in injury caused in an animal model of the disease. These effects have been translated into a human study where they have observed alterations in microbial populations and their metabolites found in systemic circulation of overweight subjects. For more information contact Nancy Turner (n_turner@tamu.edu)
10. W3122 researchers are currently developing biological markers to improve assessment of nutrition education programs, using global metabolomic profiling to detect true intake of fruits and vegetables. The overall goal is to identify those biomarkers that not only reflect intake, but that are also associated with health markers. For more information contact Tiffany Weir (Tiffany.weir@colostate.edu)
11. W3122 researchers are assessing the potential for dietary chemoprevention of cancer by phytochemicals and determination of the mechanisms of action. This work has received a great deal of attention over the past year with numerous invitations to present at national/international meetings and academic institutions as well as stories for the popular media. For more information contact Dave Williams (david.williams@oregonstate.edu)
12. W3122 researchers have demonstrated that dietary grape seed extract supplementation exerts protective effects in IBD indices of IL-10 knockout mice via multiple mechanisms and may be important as a human therapeutic for IBD. For more information contact Meijun Zhu (meijun.zhu@wsu.edu)

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Report Information

Participants

Attending the annual meeting
Benninghoff, Abby, abby.benninghoff@usu.edu (Utah State University)
Coulombe, Roger, roger@usu.edu (Utah State University)
Farnell, Yuhua, yf70@msstate.edu (Mississippi State University)
Friedman, Mendel, friedman@ars.usda.gov (USDA-ARS Albany)
Helferich, William, helferic@illinois.edu, (University of Illinois)
Nerurkar, Pratibha, pratibha@hawaii.edu (University of Hawaii)
Pestka, Jim, pestka@msu.edu (Michigan State University)
Riley, Ron, rriley@saa.ars.usda.gov (USDA-ARS Athens, GA)
Turner, Nancy, n-turner@tamu.edu (Texas A&M University)
Weir, Tiffany, tiffany.weir@colostate.edu (Colorado State University)

Reports submitted, but not able to attend annual meeting
Bello, Nicholas, ntbello@aesop.rutgers.edu (Rutgers University)
Denison, Michael, msdenison@ucdavis.edu (University of California, Davis)
Eisenstein, Richard, eisenste@nutrisci.wisc.edu (University of Wisconsin-Madison)
Guo, Mingruo, mguo@uvm.edu (University of Vermont)
Pagliarini, David, pagliarini@morgridge.org (Morgridge Institute for Research)
Williams, David, david.williams@oregonstate.edu (Oregon State University)

Brief Summary of Minutes

The 2015 Annual Meeting of the W-3122 Multistate Group was called to order by the Chair, Dr. Abby Benninghoff on the morning of October 8.  Dr. Mike Harrington (WAAESD) provided an overview of the status of the multi-state program and current funding priorities and budget status at USDA NIFA.  Last year, this group was recognized as the Western outstanding multi-state group.  Dr. Harrington would like to resubmit a nomination for W3122 to be considered for the national award again this year.  He will request updated grant totals and publications in 2016 to prepare the nomination.  Each member present delivered a presentation to update the group on his/her progress (content summarized in the Annual Group Report).  At the business meeting, new officers for 2015-2016 were selected:  Chair, Nancy Turner; Vice-Chair, Meijun Zhu; and Secretary, Yuhua Farnell.  Also, the dates for the 2016 annual meeting will be October 6-7 and the meeting will be held in Portland, Oregon.

Accomplishments

<p><strong>OBJECTIVE 1: Determine the mechanisms by which dietary bioactive compounds protect against human diseases.</strong></p><br /> <p>Dr. Roger Coulombe and colleagues are studying protective hepatic glutathione S-transferases (GST), universal phase II enzymes that detoxify dietary and environmental toxins and carcinogens such as aflatoxin B1 (AFB1) in an avian susceptibility model.&nbsp; Resistance to dietary carcinogens such as AFB₁ is strongly associated with stable expression of protective hepatic glutathione S-transferases (GST), universal phase II enzymes that detoxify dietary and environmental toxins and carcinogens such as aflatoxin B₁. Expression of GSTs is enhanced by certain dietary bioactives, such as those from Brassica vegetables. Unlike their more susceptible counterparts, wild turkeys possess functional hepatic GSTs with AFB₁ detoxification activity.&nbsp; We expressed, cloned and functionally characterized six likely candidates: GSTA genes GSTA1.1, GSTA1.2, GSTA1.3, GSTA2, GSTA3, and GSTA4 from the livers of wild and domestic turkeys.&nbsp; In contrast to their hepatic forms, all <em>E. coli</em>-expressed recombinant GSTAs from both domestic and wild turkeys, had AFBO-detoxification activity, implying that hepatic GSTs in domestic turkeys are downregulated by one or more genetic or epigenetic mechanisms.&nbsp; Focused sequencing of the hepatic transcriptome revealed significantly more hepatic GSTAs are expressed in wild than domestic birds, a difference more marked for two genes - GSTA3 and GSTA4. As in isolated populations of people with cancer susceptibility due to GST polymorphisms, loss of protective GST alleles in domestic turkeys is the likely mechanism for their extreme sensitivity compared to wild birds. This year, we initiated large-scale miRNA discovery experiments to determine whether unique miRNAs can inhibit expression of GSTA mRNAs.</p><br /> <p>After RNA sequencing of wild and domestic livers, Dr. Coulombe&rsquo;s group compiled a list of all known or predicted precursor miRNA sequences for turkey from RNACentral (179 sequences) and Ensembl (430 sequences) and filtered for duplicates. Mature miRNA sequences for these 590 unique precursor miRNAs were predicted using MatureBayes, yielding 950 unique mature miRNA sequences. BLAST databases of mRNA sequences from turkey transcriptomes were generated using RNA-seq data from our newly published data (Monson et al. 2015). The RNA-seq dataset includes transcripts of wild-type and domesticated-type turkeys treated with AFB1 and untreated controls. The Illumina reads from the four birds in each type-treatment were pooled and filtered for duplicates (while keeping track of the number of reads associated with each unique sequence). A separate BLAST database for each type-treatment was then generated from the unique RNA sequences.&nbsp; We used StarMir to predict interaction sites (both seed-pairing and seedless interactions) between the predicted mature miRNAs corresponding to those 15 precursor miRNAs and the mRNA sequences for turkey GSTA3 and GSTA4. Seven mature miRNAs had predicted interactions (with probability &gt;0.7) at sites with known SNPs between wild and domesticated mRNAs, making them candidates for further experimentation.&nbsp; Some of the eight mature miRNAs corresponding to the four precursor miRNAs identified as putative candidates using the first method were also among the seven candidates identified using the second method, so between the two methods, a total of 13 unique mature miRNAs were identified as candidates for further study.</p><br /> <p>In work completed over the past year, Dr. Benninghoff&rsquo;s research group (USU) aimed to determine whether dietary supplementation with tart cherries prevented colon tumor development in mice consuming a Western diet compared to a prudent diet. &nbsp;They hypothesized that dietary supplementation with freeze-dried whole tart cherries would suppress development of colon tumors in a model of inflammation-associated colorectal cancer. &nbsp;Mice were fed either AIN93G (optimized for rodent health) or the total Western diet (TWD), each with and without Montmorency tart cherry powder added to the diet for a total anthocyanin content of 188 mg/kg diet. &nbsp;TWD consumption markedly enhanced colitis (40-fold increase in disease activity) and tumor multiplicity (near 6-fold increase) compared consumption of the optimal AIN93G diet.&nbsp; Supplementation with tart cherry powder caused a significant 40% reduction in tumor incidence in mice fed AIN93G, whereas tart cherries had no effect on tumor incidence in mice fed TWD. &nbsp;However, tart cherry powder supplementation did not significantly affect tumor multiplicity, tumor size or colitis in mice fed either basal diet.&nbsp; The chemoprevention apparent in mice fed an optimal diet supplemented with tart cherry powder contrasted with a prior observation by Dr. Benninghoff&rsquo;s group that green tea supplementation was effective at reducing development of aberrant colonic&nbsp;crypts,&nbsp;but only in mice fed TWD.&nbsp; Thus, these observations point to important interactions between basal diets and dietary bioactive supplements and underscore the need for careful consideration of the role of basal diet in dietary chemoprevention studies in rodents. &nbsp;</p><br /> <p>Previously, Dr. Benninghoff&rsquo;s group reported that consumption of the TWD promoted tumorigenesis an inflammation-associated model of colorectal carcinogenesis.&nbsp; This year, her team completed RNAseq analysis of colon mucosa obtained from mice fed either an optimal diet, a 45% fat diet or the TWD.&nbsp; By assessing gene expression in sham mice, we were able to identify functional pathways altered by basal diet as opposed to pathways associated with carcinogenesis.&nbsp; Importantly, the 45% fat diet had very little effect on gene expression in colon mucosa compared to mice fed the optimal AIN93G diet.&nbsp; However, changes in biological processes associated with immune response were very evident in mice fed the TWD compared to both the AIN93G and 45% fat diets.&nbsp; This observation suggests that consumption of the TWD alters immune function in the colon muocsa; however, a link between this observation and colon carcinogenesis was not considered in this study design.</p><br /> <p>Dr. Pratibha Nerurkar and colleagues (University of Hawaii) have studied the anti-diabetic properties of bitter mellon (noni) juice.&nbsp; Currently, her group is focused on health disparities among enthic minorities.&nbsp; Specifically, In Hawaii, minority populations such as Native Hawaiians and Pacific Islanders (NHPI) have more than twice the rate of obesity-associated type 2 diabetes (T2D), as compared to Caucasians and more than five times as likely to die from T2D. Current therapies for obesity are complicated due to factors including an inability to maintain long-term weight loss and drug-drug interactions. In addition, conventional therapies may not be affordable, suitable and/or acceptable for culturally sensitive minority populations. There is a growing awareness and mounting body of scientific evidence, that successful implementation of strategies to control T2D among ethnic minorities will require culturally appropriate interventions.&nbsp; We have demonstrated that laboratory-prepared noni juice (fNJ) improves not only glucose and lipid metabolism, but also prevent weight gain in mice fed high-fat-diet (HFD) containing 58% fat, Although world wide market for noni products is currently estimated at $2 billion and laboratory-based research have supported health claims of noni, clinical studies supporting health benefits of noni are scan and limited to Tahitian noni juice. Current studies are planned to compare the anti-diabetic effects of fNJ and commercial noni juices and differences in chemical metabolites.</p><br /> <p>Dr. James Pestka (Michigan State University) and colleagues are investigating the impact of exposure to respiratory toxicants, such as silica, on risk for developing lupus, a debilitating autoimmune disease that adversely affects 1.5 million Americans. While the genome is a primary predisposing factor for autoimmunity, lifetime environmental exposures to factors (ie. exposome)&nbsp; such as environmental toxicants and diet are now recognized to modulate hereditary effects. Experimental animal and epidemiological studies have linked exposure to the respiratory toxicant silica to lupus and other autoimmune diseases. Importantly, nearly 2 million Americans are occupationally exposed to respirable silica.&nbsp; In contrast, both animal and clinical studies suggest that consumption of DHA and other &omega;-3 PUFAs can both prevent and resolve inflammation and autoimmune nephritis.&nbsp; Little is known about how respiratory toxicants like silica trigger lupus or how DHA supplementation could be harnessed to block environmental triggering. This critical barrier results in unnecessary lupus burden in genetically predisposed people that are exposed to respiratory toxicants. Lupus onset/progression in such individuals could potentially be mitigated by development and implementation of effective, low cost prophylactic approaches employing optimized supplementation with &omega;-3 PUFAs, already regularly consumed by over 20 million Americans. Our research focuses on using such an approach to prevent lupus.</p><br /> <p>The initiating step in lupus is loss of tolerance to nuclear self-antigens resulting in production of autoreactive antibodies and formation of circulating immune complexes. These deposit in the kidney and other organs where they promote infiltration and activation of circulating mononuclear cells, mediating advanced glomerulonephritis that can culminate in end-stage renal failure.&nbsp; In a recent investigation, Dr. Pestka&rsquo;s group used female lupus-prone NZBWF1 mice to compare dietary effects on the onset of autoimmunity as reflected by autoantibody production and glomerulonephritis in animals consuming: 1) an n-3 PUFA-rich diet containing DHA-enriched fish oil, 2)&nbsp; an n-6 PUFA-rich Western-style diet&nbsp; containing corn oil or&nbsp; 3) an n-9 monounsaturated fatty acid (MUFA)-rich Mediterranean-style diet containing high oleic safflower oil. Consumption of n-3 PUFA DHA effectively blunted the elevated autoantibody and nephritic responses in this model that were observed at 34 wk of age in mice consuming either the Western-style or Mediterranean-style diets. Remarkably, these attenuating effects co-occurred with generalized downregulation of CD4+ T cell-associated genes in the kidney and, to a lesser extent,&nbsp; in spleen that are associated with antigen presentation, T cell activation, leukocyte recruitment, B cell activation/differentiation and inflammatory responses. Many of these genes are under consideration as potential targets for development of expensive biological therapeutics for human lupus including monoclonal antibodies and receptor antagonists.</p><br /> <p>In study that was published this year, Dr. Pestka and coworkers tested the hypothesis that early repeated short-term silica exposure will modulate both latency and severity of lupus in the female NZBWF1 mouse.&nbsp; Weekly intranasal exposure to silica (0.25 and 1.0 mg) for 4 wk beginning at 9 wk of age both reduced latency and increased intensity of glomerulonephritis. silica elicited robust inflammatory responses in the lungs as evidenced by extensive perivascular and peribronchial lymphoplasmacytic infiltration consisting of IgG-producing plasma cells, and CD45R+ and CD3+ lymphocytes (B and T lymphocytes, respectively) that were highly suggestive of ectopic lymphoid tissue (ELT). In addition, there were elevated concentrations of immunoglobulins and the cytokines MCP-1, TNF-&alpha; and IL-6 in bronchoalveolar lavage fluid (BALF). silica-associated kidney and lung effects paralleled dose-dependent elevations of&nbsp; autoantibodies and proinflammatory cytokines in plasma. Taken together, silica-induced pulmonary inflammation and ectopic lymphoid neogenesis in the NZBWF1 mouse corresponded closely to systemic inflammatory and autoimmune responses as well as the early initiation of pathological outcomes in the kidney.&nbsp; These findings suggest that following airway exposure to silica, in lupus-prone mice, the lung serves as a platform for triggering systemic autoimmunity and lupus nephritis.</p><br /> <p>Dr. Nancy Turner (Texas A&amp;M University) previously demonstrated that inclusion of sorghum brans containing polyphenolic compounds in the diet influenced butyrate concentrations, suggesting that changes in the microbiota were occurring as a result of these dietary interventions. As part of a recent project, they aimed to characterize the microbiota during colitis, and ascertain if polyphenol-rich sorghum bran diets mitigate these effects (Ritchie et al., 2015a). Rats (n=80) were fed diets containing 6% fiber from cellulose, or Black (3-deoxyanthocyanins), Sumac (condensed tannins), or Hi Tannin black (both) sorghum bran. Inflammation was induced three times using 3% DSS for 48 hr (40 rats, 2 wk separation), and the microbiota characterized by pyrosequencing. The <em>Firmicutes</em>/<em>Bacteroidetes</em> ratio was higher in DSS-treated rats consuming the cellulose diet. Colonic injury negatively correlated with <em>Firmicutes</em>, <em>Actinobacteria</em>, <em>Lactobacillales</em>, and <em>Lactobacillus</em> and positively correlated with Unknown/Unclassified. After the second DSS exposure, richness was significantly lower in Sumac and Hi Tannin black. Following the third DSS treatment, <em>Bacteroidales</em>, <em>Bacteroides</em>, <em>Clostridiales</em>, <em>Lactobacillales, </em>and <em>Lactobacillus</em> were reduced, with no <em>Clostridium</em> identified. Diet significantly affected <em>Bacteroidales, Bacteroides, Clostridiales </em>and <em>Lactobacillus</em> after the second and third DSS treatment. Analysis of samples collected after the third DSS treatment demonstrated diet significantly affected all genuses, including <em>Bacteroides </em>and <em>Lactobacillus</em>, and diversity and richness increased. Sumac and Hi Tannin black DSS-treated rats had significantly higher richness compared to controls. These observations suggest that sorghum brans containing polyphenolic compounds may protect against alterations observed during colitis including reduced microbial diversity and richness, and dysbiosis of <em>Firmicutes</em>/<em>Bacteroidetes</em>.</p><br /> <p>&nbsp;Another project for Dr. Turner&rsquo;s group focused on identifying how diet and environment influences the colonic microbiota was completed and published this year (Ritchie et al., 2015b). The aim of this study was to characterize how high and low linear energy transfer (LET) radiation, microgravity, and elevated dietary iron affect colon microbiota (determined by 16S rDNA pyrosequencing) and colon function.&nbsp; Three independent experiments were conducted to achieve these goals: 1) fractionated low LET &gamma; radiation (¹³⁷Cs, 3 Gy, RAD), high Fe diet (IRON) (650 mg/kg diet), and a combination of low LET &gamma; radiation and high Fe diet (IRON+RAD) in male Sprague-Dawley rats; 2) high LET ³⁸Si particle exposure (0.050 Gy), 1/6 G partial weight bearing (PWB), and a combination of high LET ³⁸Si particle exposure and PWB in female BalbC/ByJ mice; and 3) 13 d spaceflight in female C57BL/6 mice. Low LET radiation, IRON and spaceflight increased <em>Bacteroidetes</em> and decreased <em>Firmicutes</em>. RAD and IRON+RAD increased <em>Lactobacillales</em> and lowered <em>Clostridiales</em> compared to the control (CON) and IRON treatments. Low LET radiation, IRON, and spaceflight did not significantly affect diversity or richness, or elevate pathogenic genera. Spaceflight increased <em>Clostridiales</em> and decreased <em>Lactobacillales</em>, and similar trends were observed in the experiment using a ground-based model of microgravity, suggesting altered gravity might affect colonic microbiota. Although we noted no differences in colon epithelial injury or inflammation, spaceflight elevated TGF&beta; gene expression. Microbiota and mucosal characterization in these models is a first step in understanding the impact of the space environment on intestinal health.&nbsp; Dr. Turner and colleagues are currently following up these observations by performing a controlled-land based experiment to determine the impact of high iron diets and microgravity on colon microbial populations and intestinal health.</p><br /> <p>Dr. Turner&rsquo;s most recently published work was conducted to explore the mechanisms whereby the combination of fish oil and butyrate protects against colon cancer development in our experimentally induced colon cancer model (Hong et al., 2015).&nbsp; We hypothesized that this combination protects against colon cancer initiation by decreasing cell proliferation and increasing differentiation and apoptosis through a p27^Kip1 mediated mechanism. Rats were provided diets of corn or fish oil, with/without butyrate, and terminated 12, 24 or 48 h post azoxymethane (AOM) injection. Proliferation (Ki-67), differentiation (Dolichos Biflorus <em>Agglutinin</em>), apoptosis (TUNEL) and p27^Kip1 (cell cycle mediator) were measured in the same cell within crypts in order to examine the coordination of cell cycle as a function of diet. DNA damage (N⁷-methylguanine) was determined by quantitative immunohistochemical analysis. Dietary fish oil decreased DNA damage by 19% (P=0.001) and proliferation by 50% (P=0.003) and increased differentiation by 56% (P=0.039) compared to corn oil. When combined with butyrate, fish oil enhanced apoptosis 24 h post AOM injection compared to a corn oil/butyrate diet (P=0.039). There was an inverse relationship between crypt height and apoptosis in fish oil/butyrate group (r= -0.53, P=0.040). Corn oil/butyrate group showed a positive correlation between p27^Kip1expression and proliferation (r= 0.61, P=0.035). These results indicate the in vivo effect of butyrate on apoptosis and proliferation is dependent on dietary lipid source. These results demonstrate the presence of an early coordinated colonocyte response by which fish oil and butyrate protects against colon tumorigenesis.</p><br /> <p>Dr. Turner continues to work towards understanding the impact of sorghum bran bioactive compounds on circulating metabolites in overweight subjects.&nbsp; Results from their untargeted metabolomics analyses suggested there was a possibility of changes in lipoprotein metabolism.&nbsp; As a result, they worked with Dr. Walzem to perform a detailed lipoprotein fraction analysis.&nbsp; From this work they identified changes in three of the LDL subfractions and one of the HDL subfractions after our subjects consumed the low or high level of sumac sorghum cereal.&nbsp; The mixture of changes detected was suggestive of a reduced risk of cardiovascular disease in obese subjects.&nbsp;</p><br /> <p>Finally, Dr. Turner and colleagues completed an experiment to determine the impact of dried plums, a fiber and bioactive compound rich food source, on colon carcinogenesis.&nbsp; They discovered that including the dried plums in the diet at a level that would correspond to the human equivalent serving size effectively reduced the formation of early preneoplastic lesions by 50%.&nbsp; We detected significant changes in the distal colon microbiota of rats consuming the control diet.&nbsp; However, rats consuming the dried plum diet exhibited minimal changes in the microbial populations between the proximal and distal colon, and the data indicated that changes in colon microbiota induced by the carcinogen were not as prominent in the dried plum group, when compared to the control diet group.&nbsp; They are following up this project by performing untargeted metabolomics analyses on feces collected from the proximal and distal colon to determine if the changes in microbiota resulted in altered metabolite profiles, which may help explain suppression of colon tumorigenesis in those rats.&nbsp; In addition, Dr. Turner is now collaborating with Dr. Ruth Globus who is determining the impact of dried plums on radiation damage to bones.&nbsp; They are acquiring feces and colon tissue samples from those animals and will be determining if this dietary intervention serves to reduce the impact of radiation on colon health and microbial populations.</p><br /> <p>Dr. Tiffany Weir&rsquo;s laboratory (Colorado State University) continued to explore the relationship between bioactive dietary components and their metabolism by gut bacteria as well as how they effect gut microbial composition for disease prevention. Recent research, including a human study conducted by the Weir laboratory, has shown that stool microbes and microbial metabolites differ between healthy individuals and those with colorectal cancer (CRC) (Weir et al., PLoS One 2013).&nbsp; In a healthy human cohort, they demonstrated the feasibility of increasing dietary rice bran consumption for CRC prevention. Rice bran has a number of phytochemical components that contribute to reported anti-inflammatory and anti-carcinogenic bioactivities and could be utilized as a dietary component for chemoprevention. Dr. Weir and her colleagues showed that, in a healthy population, incorporation of dietary rice bran does not cause a large-scale disturbance in the intestinal ecosystem, but may induce subtle changes to the microbiota and metabolites detected in stool samples. The changes that they observed included increases in certain beneficial commensal bacteria and the introduction of bioactive metabolites (both through the diet and through microbial metabolism) that may reduce inflammation and contribute to CRC chemoprevention (Sheflin et al., Nutrients 2015). Further examination of the microbial changes introduced by rice bran consumption in a cohort of CRC survivors showed that there was increased production of the SCFA acetate by gut bacteria. Acetate is important in regulation of glucose metabolism and lipogenesis, modulating intestinal transit, and appetite regulation through interaction with intestinal G-coupled protein receptors, GPR41 and GPR43 in the intestinal epithelium and adipose tissue. Results of microbial sequencing in stool suggest transient increases in <em>Bacteroides ovatus</em>, which is a known butyrate producer, as well as in total bacterial diversity. Bacterial diversity has been shown to be inversely correlated with CRC occurrence. However, CRP levels were significantly increased in individuals consuming rice bran, so the actual benefits of RB consumption in terms of modulating intestinal inflammation need further exploration. Finally, examination of individual participant changes to microbiota suggest that there were responders and non-responders to the diet intervention and further work is needed to determine the factors involved in predicting responses. Metabolite data from pilot study healthy individuals has allowed us to refine rice bran-specific metabolite targets and the levels of these metabolites is currently being explored in stool.</p><br /> <p>Other ongoing projects by Dr. Weir&rsquo;s group include examining the effects of caffeine on DNA repair mechanisms in enteric pathogens, identifying biomarkers in urine and stool that are consistent with fruit and vegetable intake levels as well as increased phytochemical consumption of intestinal bacteria composition and function, determining ability of fuzhuan tea metabolites to regulate cholesterol metabolism pathways in both preventive and reversal animal models, and identifying the ability of hops phytoestrogens to mitigate microbial dysbiosis and altered metabolism resulting from loss of estrogen.</p><br /> <p>Dr. Nicholas Bello and colleagues (Rutgers University) studied a ketone [4-(4-hydroxyphenyl)-2-butanone] derived from red raspberry (<em>Rubus idaeus</em>), which has purported antiobesity properties. Despite the popular press coverage of this proclaimed &ldquo;miracle fat burner in a bottle&rdquo; and huge internet sales, the safety, efficacy, and mechanism of action of raspberry ketone as a weight loss supplement are still unclear. While several studies have demonstrated lipolytic activity for raspberry ketone <em>in vitro</em>, there are only two <em>in vivo </em>studies in rodents that have examined the ability of raspberry ketone to prevent obesity and reduce dyslipidemia. The purpose of these set of experiments was to determine whether raspberry ketone suppressed feeding behavior and whether the compound activated feeding-related neural pathways. They determined that raspberry ketone provided via oral gavage at 200mg/kg bw significantly decreased food intake by about 20% compared to mice dosed with 100 mg/kg or provided vehicle only, and that the suppression was evident from 0.5 to 24 hours post dosing.&nbsp; The effect of raspberry ketone was apparently not linked to gastrointestinal illness. In order to determine whether raspberry ketone acts on the central controls of feeding, Dr. Bellow and coworkers examined the neural activation by c-Fos immunoreactivity following acute dosing (200 mg/kg) in the hindbrain and hypothalamus. They found a significant increase in the number of c-Fos positive cell in the nucleus of the solitary tract (NTS) in mice that received raspberry ketone compared to controls. In the arcuate nucleus of the hypothalamus, there were no differences in the number of positive cells between treatments.&nbsp;&nbsp;&nbsp;&nbsp;</p><br /> <p>Dr. Richard Eisenstein (University of Wisconsin, Madison) and coworkers are determining the extent to which diet-induced obesity and iron overload activate similar signaling pathways that contribute to the individual disease etiology.&nbsp; One goal of their work to understand the mechanistic basis of the mild anemia observed in obesity.&nbsp; A related goal is on the so-called unfolded protein response (UPR) and signaling pathways down-stream of the UPR that may modulate production of the iron regulatory protein hepcidin.&nbsp; Dr. Eisenstein&rsquo;s group is currently focused on the diet-induced obesity aspect of this work.&nbsp; It is well accepted that this model leads to activation of the UPR and we will be examining, in samples obtained in the last year, if UPR components such as the protein kinase PERK, a endoribonuclease IRE1 and the transcription factor XBP1 are activated.&nbsp; They are also examining the iron status of the control and obese mice in order to relate activation of the UPR to changes in iron metabolism.&nbsp; A key component of this is the liver derived peptide hepcidin which controls dietary iron absorption and iron recycling from old red cells by macrophages.&nbsp; Evidence in the literature indicates that hepcidin expression is activated by the UPR. Activation of the UPR in obese subjects could stimulate hepcidin production which is predicted to reduce dietary iron absorption and iron recycling leading to anemia.&nbsp; A final component of this work is to examine if expression of the transcription factor HIF2-alpha is altered in obese mice.&nbsp; HIF2alpha expression is controlled at the translational level by iron and we hypothesis the UPR.&nbsp; Some evidence suggests that HIF2alpha may control transcription of the hepcidin gene.&nbsp; Our current study will allow us to examine if there is activation of the UPR in obese mice is associated with translational dysregulation of HIF2alpha mRNA and alterations in hepcidin gene expression.</p><br /> <p>Dr. Eisenstein and colleagues are also examining how the iron regulated RNA binding protein, iron regulatory protein 1 (IRP1), controls dietary iron absorption and erythropoiesis during early postnatal development.&nbsp; An ultimate goal of this, and a subject of our recently submitted Hatch renewal proposal, is whether dietary factors known to control HIF2alpha expression might consequently control dietary iron absorption.&nbsp; IRP1 is the key iron mediator of HIF2alpha mRNA translation.&nbsp; IRP1 is a repressor of HIF2alpha synthesis and loss of IRP1 translationally activates HIF2alpha mRNA.&nbsp; HIF2alpha is a transcriptional activator of the main blood forming hormone erythropoietin and also the iron transport system controlling dietary iron acquisition in the duodenum.&nbsp; Mice lacking IRP1 develop a severe but transient polycythemia (too many red cells) and absorb more iron to promote red cell overproduction.&nbsp; They recently found that these mice have very strongly repressed hepcidin mRNA at birth and we are examining whether this involves canonical or non-canonical (HIF2alpha) mechanisms for controlling hepcidin gene transcription.&nbsp; In addition, they are currently determining the extent to which HIF2alpha-targeted intestinal iron transport genes are altered in neonatal mice lacking IRP1.&nbsp; These studies will expand the understanding as to how dietary iron absorption is controlled during the neonatal period with a specific focus on how the efficiency of iron absorption may be controlled to limit development of iron deficiency and prevent over-absorption of iron in common iron-loading disorders.&nbsp; Dr. Eisenstein is also examining the iron-dependent mechanisms controlling IRP1 function as a means to understand how dietary iron absorption is controlled in disease states including iron deficiency as well as in inflammatory disorders.&nbsp;&nbsp; This includes the known impact of inflammatory scenarios in reducing intestinal iron absorption.&nbsp; The ability of IRP1 to bind mRNA is determined by insertion or loss of an Fe-S cluster with the cluster-free apoprotein form binding RNA. A second mechanism involves iron-dependent degradation of the IRP1 apoprotein.&nbsp; To better understand how dietary iron absorption if controlled we are focusing on the ability of IRP1 to be regulated by the Fe-S cluster vs. the protein degradation mechanism.&nbsp; A manuscript on this work is in preparation.</p><br /> <p>Dr. Mendel Friedman (USDA-ARS Albany) showed that the tomato glycoalkaloid &alpha;-tomatine induces cell death in mouse colon cancer ct-26 cells and transplanted tumors in mice.<strong>&nbsp; </strong>Tomatoes (<em>Solanum lycopersicum</em>) produce the bioactive glycoalkaloid &alpha;-tomatine. This study determined the effect of commercial &alpha;-tomatine on CT-26 colon cancer cells in vitro and in vivo in an intracutaneously transplanted mouse tumor. Cytotoxicity experiments showed that &alpha;-tomatine induces about 50% lysis of the colon cancer cells at 3.5 &mu;M after 24 h of treatment. Intraperitoneally administered &alpha;-tomatine (5 mg/kg body weight) also markedly inhibited growth of the tumor using CT-26 cancer cells without causing body and organ weight changes. The reduced tumor growth in the mice by 38% after 2 weeks was the result of increased caspase-independent apoptosis associated with increased nuclear translocation of apoptoosis-inducing mitochondrial protein (AIF) and decreased survivin expression in tumor tissues. &alpha;-Tomatine in pure form and in tomatine-rich green tomatoes might prevent colon cancer.</p><br /> <p>&nbsp;Dr. Friedman also investigated the effect of allyl isothiocyanate on developmental toxicity in exposed <em>Xenopus laevis</em> embryos. The pungent natural compound allyl isothiocyanate isolated from the seeds of Cruciferous (Brassica) plants such as mustard is reported to exhibit numerous beneficial health-promoting antimicrobial, antifungal, anticarcinogenic, cardioprotective, and neuroprotective properties. Because it is also reported to damage DNA and is toxic to aquatic organisms, the objective of the present study was to determine whether it possesses teratogenic properties. The frog embryo teratogenesis assay-.<em>Xenopus</em> (FETAX) was used to determine the following measures of developmental toxicity of the allyl isothiocyanate: (a) 96-h LC50, defined as the median concentration causing 50% embryo lethality; (b) 96-h EC50, defined as the median concentration causing 50% malformations of the surviving embryos; and (c) teratogenic malformation index (TI), equal to 96-h LC50/96-h EC50. The quantitative results and the photographs of embryos before and after exposure suggest that allyl isothiocyanate seems to exhibit moderate teratogenic properties.</p><br /> <p>&nbsp;Dr. David Pagliarini at the Morgridge Institute for Research (Madison, WI) has have continued to investigate the effects of iron deprivation on the cellular control of mitochondrial biogenesis. His group previously discovered, using microarray and quantitative mass-spectrometry approaches, that depriving C2C12 mouse myotubes of iron, through treatment with the iron chelator deferoxamine (DFO) leads to a global decrease in the transcript abundance of mitochondrial- and nuclear-encoded mitochondrial genes and mitochondrial proteins. They found that this response to iron chelation is universal across a broad range of cell types, rapid (occurring within 24 hours) and dose-dependent. Additionally, they discovered that the effect on cellular gene expression and respiratory capacity can be fully reversed upon the reintroduction of iron, indicating that the response to iron deprivation is an adaptive cellular response rather than irreversible cellular damage. Lastly, they showed that this process is independent of well-established regulators of mitochondrial biogenesis, including PGC-1&alpha;, PGC-1&beta; and HIF-1&alpha;. These results were published in the 2013 January issue of <em>Cell Reports</em>.</p><br /> <p>Following this publication, Dr. Pagliarini and colleagues continued their strategy of using large-scale, unbiased genomic and proteomic analyses in combination with targeted, hypothesis driven experiments to elucidate the molecular basis of this adaptive cellular response. First, they performed detailed timecourse measurements of mitochondrial transcript and protein levels following iron deprivation, quantified using RT-qPCR and immunoblotting respectively. From this timecourse, they found that the decrease in OxPhos (oxidative phosphorylation) proteins preceded the decrease in their corresponding transcripts. Additionally, they discovered that for the few OxPhos proteins that are unaffected by our iron chelation treatment (complexes III and V), their transcripts were nonetheless reduced (and that this observation is supported by our original microarray and mass spectrometry analyses). These results suggest that either the changes in mitochondrial transcript and protein levels occur though two separate mechanisms <em>or</em> that the changes in transcript abundance are in response to the protein changes, possibly through a retrograde signaling event. Next, Dr. Pagliarini and colleagues determined the level of gene expression at which iron deprivation operates (i.e., transcription or mRNA turnover) to cause the observed decrease in mitochondrial transcripts. To do so, they utilized RNA pulse-chase and labeling approaches, and from these analyses, determined that iron deprivation affects the synthesis of new OxPhos-encoding transcripts but has no measurable effect on transcript turnover.</p><br /> <p>Further, using a MS-based quantitative proteomics approach in collaboration with Professor John Denu&rsquo;s lab (Biomolecular Chemistry, UW-Madison), Dr. Pagliarini and coworkers discovered that iron chelation causes dynamic changes in histone acetylation and methylation (including an overall decrease in histone acetylation) and have validated these observations via immunoblotting of histone extracts. They also found that the effect of iron chelation on transcript levels is fully reversed with (histone deacetylase) HDAC inhibition, consistent with histone post-translational modification (PTM)-mediated regulation of gene expression. To determine if changes in these modifications are found at nuclear-encoded mitochondrial genes whose expression is affected by iron deprivation, they performed chromatin immunoprecipitation (ChIP)-qPCR analyses. From these experiments, they observed reduced levels of histone acetylation at all mitochondrial genes analyzed, indicating a direct regulatory link between a decrease in histone acetylation and mitochondrial gene expression in response to iron deprivation.</p><br /> <p>In addition to the experiments above, Dr. Pagliarini&rsquo;s group utilized both microarray and quantitative mass spectrometry approaches to identify potential novel protein regulators involved in the iron response. As expression changes in potential regulators of the response are likely to occur before the changes in mitochondrial gene expression, we collected samples for these analyses at an early time point (12 hours) following DFO treatment, prior to any observable mitochondrial change. They are currently performing loss- and gain-of-function analyses on potential regulators identified from these experiments. Using a candidate-based approach, we investigated the role of the major mitochondrial quality control proteases (Lon, HtrA2, ClpXP, <em>i</em>-AAA, <em>m</em>-AAA) in the observed response using RNAi and CRISPR/Cas9-mediated gene silencing. From this analysis we found that knockdown of these proteases did not affect the decrease in abundance of mitochondrial proteins following iron chelation. Last, they tested whether the mechanistic/mammalian target of rapamycin (mTOR), a protein kinase that can regulate mitochondrial biogenesis and through multiple mechanisms, is involved in the iron response. Surprisingly, treatment of cells mTOR inhibitors did not cause a decrease in OxPhos proteins and DFO treatment did not cause any changes in phosphorylation of the mTOR targets. Moreover, when cells were treated simultaneously with DFO and mTOR inhibitors, DFO caused the same decreases in OxPhos proteins, suggesting that the effect of iron deprivation on mitochondrial proteins is independent of mTOR activity and its downstream regulatory processes.</p><br /> <p>In Dr. David Williams&rsquo; laboratory (Oregon State University), the focus of this research continues to be on dietary chemoprevention of cancer, specifically protection of the fetus/infant from transplacental carcinogens by dietary supplementation with plant phytochemicals or the whole foods from which they were derived.&nbsp; The emphasis continues to be on phytochemicals from cruciferous vegetables primarily indole-3-carbinol (I3C) and sulforaphane (SFN).&nbsp; Dr. Williams and colleagues have recently explored the potential for I3C and SFN, added to the maternal diet during pregnancy, to protect the fetus/infant from transplacental cancer caused by an important class of environmental chemical pollutants, the polycyclic aromatic hydrocarbons (PAHs).&nbsp; It has been estimated that 95% of exposure (for a non-smoker) to carcinogenic PAHs is through diet.&nbsp; We found epigenetic markers such as DNA methylation, histone acetylation and profiles of non-coding RNAs were markedly altered in newborns from mothers exposed to a carcinogenic PAH in her diet and these alterations in the epigenome could be partially ameliorated by maternal dietary I3C.</p><br /> <p><strong>OBJECTIVE 2. Elucidate mechanisms of action of dietary toxicants and develop biomarkers for human risk assessment and disease prevention.</strong></p><br /> <p>Dr. William Helferich and colleagues (University of Illinois) developed a breast cancer metastasis model in which mammary tumor cells are injected into the marrow cavity of mice and metastasis to lung is followed by bioluminescent imaging (BLI).&nbsp; This model can be used to evaluate pharmacological and dietary interventions to suppress cancer metastasis.&nbsp; Breast cancer (BC) is the leading cancer in women worldwide. Metastasis occurs in stage IV BC with bone and lung being common metastatic sites. Bone is one of the most common sites for metastasis in breast cancer (BC). Micrometastasis in bone marrow was detected in 30% of patients with stage I, II, or III BC at time of primary surgery and is a strong indicator of poor prognosis. Aromatase inhibitors (AI) like letrozole suppress the conversion of androgens to estrogens and inhibit estrogen-responsive mammary tumor growth. The goal of this study was to evaluate the effects of letrozole on BC micro-metastatic tumor growth in bone and lung metastasis in intact and ovariectomized (OVX) mice with murine estrogen receptor negative (ER-) BC cells inoculated in tibia. Forty-eight BALB/c mice were randomly assigned to one of four groups: OVX, OVX+Letrozole, Intact, and Intact+Letrozole, and injected with 4T1 cells intra-tibially. Letrozole was subcutaneously injected daily for 23 days at a dose of 1.75 &micro;g/g body weight. Tumor progression was monitored by bioluminescence imaging. OVX mice had lower serum estradiol than intact mice and greater tumor area and integrated density in the inoculated limb on D14 and D17. Letrozole decreased serum estradiol levels and reduced lung surface tumor numbers in intact animals. Mice receiving letrozole had significantly fewer tumor colonies and fewer proliferative cells in the lung than OVX and intact controls based on H&amp;E and Ki-67 staining, respectively. In conclusion, tumors were larger with greater integrated density in inoculated limbs of OVX animals and letrozole reduced BC metastases to lungs, suggesting that though 4T1 cells are considered estrogen unresponsive, by lowering systemic estrogen level and possibly through interacting with the host organ, breast cancer metastasis to the lung was still effectively reduced by the aromatase inhibitor letrozole. Therefore, Letrozole may reduce bone micrometastasis to lung in the preclinical model and further investigations are needed before any recommendations are made to BC survivors.</p><br /> <p>Deoxynivalenol (DON or "vomitoxin"), a trichothecene mycotoxin produced by Fusarium, is a global food safety concern because it commonly contaminates cereal grains and has the potential to cause growth suppression and gastrointestinal disease in humans. Climate change, modified agricultural practices and recent globalization of trade in agricultural plants have increased Fusarium cereal blight, thereby greatly increasing grain contamination by DON and markedly expanding the contaminant profile to include other structurally-related 8-ketotrichothecenes (3-ADON, 15-ADON, nivalenol, fusarenon X) well as plant glucosidic metabolites such as DON-3-glucoside. Existing data are insufficient to predict the toxicity risks from exposure to mixtures in these emerging trichothecenes. Dr. Pestka and colleagues (MSU) tested the hypothesis that toxic equivalency factors (TEFs) for the 8-ketotrichothecenes derived from DON toxicity models will be applicable to food safety risk assessment and toxicity analysis.&nbsp; This is being achieved in three ways. First, they compared the anorectic potencies of the the 8-ketotrichothecenes relative to DON using a mouse food refusal bioassay and relating this to the aberrant secretion of the gastrointestinal hormones peptide YY (PYY) and cholecystokinin (CCK). Second, they are ascertaining the comparative emetic potencies of 8-ketotrichothecenes relative to DON using a mink vomiting bioassay and are relating these data to the elevated secretion of gastrointestinal hormone PYY as well as serotonin. Finally, they are applying this knowledge by developing simple in vitro assay that will enable measurement of the trichothecene toxic equivalents in food samples for use as an intervention tool. Toward this end, several candidate enteroendocrine cell lines and endpoints (calcium mobilization, hormone secretion) have been identified.</p><br /> <p>Dr. Ron Riley (USDA-ARS Athens, GA)&nbsp; investigated histone deacetylase inhibition in mouse embryonic fibroblasts from a fumonisin NTD-succeptible mouse model.&nbsp; Studies have been completed showing that the target of the fumonisin-induced elevation in sphingoid base 1-phosphates and the sphingosine 1-phosphate analog FTY720-P is histone deacetylase. This is important because human exposure to histone deacetylase inhibitors during pregnancy causes neural tube defects (NTDs) in mice and both FTY720 and fumonisin B1 cause NTDs in mice.&nbsp; Accumulation of nuclear Sa 1-P, reduction in histone deacetylase activity, and increased acetylation of specific histones represents a plausible mechanism for fumonisin exposure as a risk factor for NTDs in humans.&nbsp; The information from in vivo mouse studies, in vitro studies in mouse, and human neural progenitor cells, and the finding that consumption of corn contaminated with high levels of fumonisin B1 is correlated with elevated sphinganine 1-phosphate in Guatemalan women, a country with high incidence of NTD, provides evidence that supports the hypothesis that consumption of corn-based diets containing high levels of fumonisin B1 could be a possible risk factor for NTDs in humans.&nbsp; Dr. Riley also conducted metabolism studies of fumonisin B1 in rats.&nbsp; A manuscript describing for the first time the in vivo metabolism of fumonisin B1 to ceramide like compounds has been published. The findings show that bioavailability of fumonisin B1 is higher than previously shown with significant amounts of the metabolites, relative to parent compound, accumulating in liver.&nbsp; Characterizing metabolism and the biological activity(ies) of the metabolites is needed to better understand mechanisms of action and improve risk assessments.&nbsp;</p><br /> <p>Dr. Riley and colleagues also determined that fumonisin exposure women was linked to inhibition of an enzyme that is a key event in farm and laboratory animal diseases.&nbsp; Fumonisin B₁ (FB₁) is a toxic chemical produced by molds.&nbsp; The molds that produce fumonisin are common in corn.&nbsp; Consumption of contaminated corn by farm animals has been shown to be the cause of disease.&nbsp; Fumonisin has been hypothesized to be an environmental risk factor for diseases in humans in countries where corn is a dietary staple and infection with the mold is likely. In order to determine if fumonisin contributes to disease in humans, methods were developed to measure changes in the urine and blood levels of chemicals that are indicators of changes indicative of pre-disease states in animal studies.&nbsp; The human studies have focused on populations in Guatemala where corn is a dietary staple.&nbsp; Intake of fumonisin in these populations can be very high.&nbsp; Corn, urine and blood were sampled from over 1500 women and the results show that fumonisin intake and changes in a unique class of fats (sphingoid base 1-phosphates) in the blood are correlated in a manner that mimics the effects of fumonisin in laboratory animals.&nbsp; The findings are consistent with the hypothesis that fumonisin inhibits the same enzyme in humans as it does in farm and laboratory animals consuming diets high in fumonisin.&nbsp; These findings are the basis for development of biomarker-based studies in humans designed to identify possible human diseases where fumonisin could be a contributing factor and will provide an incentive to reduce fumonisin exposure in developing countries where corn is a dietary staple. These studies were conducted as part of a collaboration between USDA-TMRU (Athens, GA), Centro de Investigaciones en Nutrici&oacute;n y Salud in Guatemala, Creighton University and Duke University.&nbsp; Additional human fumonisin biomarker-based studies are in progress in collaboration with Oakland University, Centro de Investigaciones en Nutrici&oacute;n y Salud (CIENSA), Michigan State University, and the University of Georgia.&nbsp;&nbsp; The Oakland University study is focused in the Department of Huehuetenango (Guatemala), the CIENSA study is focused on the Departments of Guatemala and Alta Verapaz (Guatemala), the Michigan State University study is focused on Nepal and Tanzania, and the University of Georgia study is focused in Texas. The study in Huehuetenango is near completion and the results provide additional evidence for a link between fumonisin exposure and disruption of sphingolipid metabolism in humans.</p><br /> <p>Dr. David Williams&rsquo; group currently focuses on mechanisms of action and biomarkers associated with an important class as (3 of the top 10 ATSDR (Agency for Toxic Substances Disease Registry, a component of the CDC) environmental chemicals of concern are PAHs.&nbsp; These have included molecular biomarkers such as alterations in levels of tumor suppressor genes, DNA adductions, etc., in addition to biological endpoints. Our group has been the first to utilize accelerator mass spectrometry (Lawrence Livermore National Laboratory, LLNL) to follow the uptake and elimination of PAHs at an environmentally relevant level of exposure (10% or less of average daily exposure).&nbsp; Using this technology, we can measure femto(10^-15) grams of PAH/ml of blood. Ten femtograms/ml of blood is equivalent to 1 drop of water in 4000 Olympic-sized swimming pools.</p><br /> <p><strong>OBJECTIVE 3. Discover and characterize novel bioactive dietary compounds that have beneficial or adverse effects on human health.</strong></p><br /> <p>Dr. Benninghoff&rsquo;s group (USU) completed a small pilot study initiated by a local high school student with an interest in dietary interventions for treatment of diabetes, specifically a Mexican folk remedy of incorporating canary seed into the diet to reduce glucose levels and improve insulin resistance. They tested the efficacy of canary seed supplementation for prevention of diet-induced glucose intolerance in mice fed a normal diet, a 60% high fat diet (to induce metabolic syndrome) and a high fat diet + 1% canary seed (CS). As expected, mice fed the high fat and high fat+canary seed diet experienced increased weight gain, primarily as excess fat. However, addition of canary seed to the high fat diet did not prevent excess weight gain or ameliorate the symptoms of diet-induced diabetes, as determined by elevated fasting glucose levels and glucose intolerance.&nbsp; These observations contradict those reported previously by Perez Gutierrez (2014, Evidence-Based Complementary and Alternative Medicine, article ID 145901), although the experimental models were notably different; specifically, the current experiment evaluated CS as a preventative agent, while the Perez Gutierrez study used a therapeutic approach.</p><br /> <p>Dr. Michael Denison (UC Davis) and colleagues have continued to develop new and improved recombinant cell-based CALUX (chemically-activated luciferase expression) bioassays for screening of chemicals and extracts in order to detect and identify natural and synthetic activator/inhibitors of the Ah receptor (AhR) or steroid hormone receptors (i.e. estrogen receptor (ER)).&nbsp; They successfully used these bioassay systems for the detection and characterization of food and herbal extracts for these chemicals, but these assays are not optimal in several respects and need improvement to expand and enhance their application for extracts of food and environmental samples.&nbsp; Over the past year, they developed two improved CALUX assays for detecting agonists and antagonists for the AhR or ER that will greatly facilitate the detection and identification of chemicals that can interact with these receptor systems.&nbsp; They previously developed an estrogen-responsive recombinant human ovarian (BG1Luc4E2) cell line recently accepted by the US Environmental Protection Agency (USEPA) and Organization for Economic Co-operation and Development (OECD) as an officially accepted bioanalytical method to detect agonists/antagonists. Unfortunately, these cells appear to contain only one of the two known ER isoforms, ERa but not ERb, and the differential ligand selectivity of these ERs indicates that the currently accepted screening method only detects a subset of total estrogenic chemicals. To improve the estrogen screening bioassay, BG1Luc4E2 cells were stably transfected with an ERb expression plasmid and positive clones identified using ERb-selective ligands (genistein and Br-ERb-041). A highly responsive clone (BG1LucERbc9) was identified that exhibited greater sensitivity and responsiveness to ERb-selective ligands than BG1Luc4E2 cells, and quantitative reverse-transcription polymerase chain reaction confirmed the presence of ERb expression in these cells. Screening of pesticides and industrial chemicals identified chemicals that preferentially stimulated ERb-dependent reporter gene expression. Together, the results of these studies not only demonstrate the utility of this new dual-ER recombinant cell line for detecting a broader range of estrogenic chemicals than the current BG1Luc4E2 cell line, but screening with both cell lines allows identification of ERa and ERb-selective chemicals.</p><br /> <p>In contrast, the AhR-responsive CALUX cell bioassay is commonly used for rapid screening of samples for the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), dioxin-like compounds, and AhR agonists/antagonists. This cell line has been used to detect such chemicals in a diverse array of matrices from environmental and biological samples, to food and commercial consumer products.&nbsp; However, the limits of the lower sensitivity of this bioassay have restricted the application of this assay since even lower concentration of these compounds need to be detected.&nbsp; Accordingly, we previously generated a novel third generation (G3) recombinant AhR-responsive mouse CALUX cell line (H1L7.5c3) with a significantly enhanced response to dioxin-like chemicals (DLCs) compared to existing AhR-CALUX cell bioassays. However, the elevated background luciferase activity of these cells and the absence of comparable G3 cell lines derived from other species (particularly that of human) have limited their utility for screening purposes. Thus, Dr. Denison&rsquo;s group developed and characterized several new species-specific G3 recombinant AhR-responsive CALUX cell lines (human, rat and guinea pig) that exhibit significantly improved limit of detection and dramatically increased TCDD induction response. The low background luciferase activity, low minimal detection limit (0.1 pM TCDD) and enhanced induction response of the rat G3 cell line (H4L7.5c2) over the H1L7.5c3 mouse G3 cells, identifies them as a more optimal cell line for screening purposes. The utility of the new G3 CALUX cell lines were demonstrated by screening sediment extracts and a small chemical compound library for the presence of AhR agonists. The availability of new G3 CALUX cell lines with dramatically improved limit of detection and increased response will improve and enhance our ability to identify DLCs and AhR agonists/antagonists in a broader range of samples with low levels of contamination and/or in small sample volumes.</p><br /> <p>&nbsp;Dr. Denison has also collaborated with numerous other investigators to demonstrate the presence of natural and synthetic DLCs and estrogenic chemicals in a variety of different matrices.&nbsp; In addition, <em>Malassezia furfur</em> yeast strains isolated from human skin preferentially biosynthesize indole alkaloids which can be detected in human skin and are highly potent activators of the AhR and AhR-dependent gene expression. Chemical analysis of an EtOAc extract of a <em>M. furfur</em> strain obtained from diseased human skin and grown on <em>L</em>-tryptophan agar revealed several known AhR active tryptophan metabolites along with a previously unidentified compound, pityriazepin. While its structure resembled that of the known alkaloid pityriacitrin, the comprised pyridine ring had been transformed into an azepinone. The indoloazepinone scaffold of pityriazepin is extremely rare in nature and has only been reported once previously. Pityriazepin, like the other isolated compounds, was found to be a potent activator of the AhR-dependent reporter gene assays in recombinant cell lines derived from four different species, although significant species differences in relative potency was observed. The ability of pityriazepin to competitively bind to the AhR and directly stimulate AhR DNA binding classified it as a new naturally-occurring potent AhR agonist. <em>Malassezia furfur</em> produces an expanded collection of extremely potent naturally occurring AhR agonists, which produce their biological effects in a species-specific manner.</p><br /> <p>Dr. Mendel Friedman (USDA-ARS Albany) determined that rice hull liquid smoke protects fat mice against obesity. Obesity and being overweight are consequences of excessive adipogenesis.&nbsp; In the United States, it is estimated that&nbsp; about 80 million adult individuals are obese. In a collaborative study, we discovered that a rice hull liquid smoke extract exhibited strong anti-adipogenic effects in adipocytes (fat cells). The in vitro anti-obesity effect was confirmed in a 7-week mice feeding study. The extract prevented mice on the high-fat diet from gaining weight, caused significant reductions in total serum and liver cholesterol and triglyceride levels, and protected against liver injury, suggesting that the liquid smoke extract might inhibit obesity in humans. The liquid smoke extract, which seems to be safe for mice, could be added to different food categories (cheese, meat, seafood) using methods for the incorporation of wood-derived liquid smoke. US producers of liquid smoke should produce and market the rice hull smoke as a health-promoting food additive.</p><br /> <p>In other work, Dr. Friedman showed that rice hull smoke extract protects mice against a Salmonella lipopolysaccharide-induced endotoxemia.&nbsp; Endotoxemia (sepsis, septic shock) is an inflammatory, virulent disease that results mainly from infection by Gram-negative bacteria. The present study investigates the inhibitory effects of a rice hull smoke extract (RHSE) against murine endotoxemia induced by Salmonella lipopolysaccharide and d-galactosamine (LPS/GalN). Pretreatment of the mice with RHSE via dietary administration for 2 weeks resulted in the suppression (in %) of LPS/GalN-induced catalase by 70.7, superoxide dismutase (SOD) by 54.6, and transaminase (GOT/GPT) liver enzymes by 40.6/62.5, the amelioration of necrotic liver lesions, and the reduction of tumor necrosis factor-&alpha; (TNF-&alpha;) by 61.1 and nitrite serum level by 83.4, as well as myeloperoxidase (MPO) enzyme associated with necrotic injury of the lung and kidney by 65.7 and 63.3, respectively. The RHSE also extended the lifespan of the toxemic mice. The results using inflammation biomarkers and from the lifespan studies suggest that the RHSE can protect mice against LPS/GalN-induced liver, lung, and kidney injuries and inflammation by blocking oxidative stress and TNF-&alpha; production, thereby increasing the survival of the toxic-shock-induced mice. It seems that the smoke extract also has the potential to serve as a new multifunctional resource in human food.<strong>&nbsp;</strong></p><br /> <p><strong>OBJECTIVE 4. Increase beneficial or decrease adverse effects of bioactive constituents and microbes in food.</strong></p><br /> <p>Dr. Mendel Friedman (USDA-ARS Albany) and colleagues determined that an elm tree bark bioprocessed in a liquid culture of mushroom mycelia protects mice against asthma. Asthma is a multifaceted chronic inflammatory disease of the lung airways, resulting in bronchial hyper-responsiveness following exposure to an allergen. There is no cure. Protein biomarkers can serve as a powerful detection tool in both clinical and basic research applications. The results of the present study with asthma-associated biomarkers (cytokines in serum and bronchoalveolar fluid, serum IgG and other biomarker levels, and inflammatory cell infiltration in the trachea and lungs) as well as RT-PCR and Western blot analysis of associated genes all show that the bioprocessed bark of the elm tree in a liquid mushroom mycelia culture normalized antigen-triggerred immune imbalance of the two T-helper proteins (Th1/Th2) in an mouse asthma model, suggesting that the treatment overcame&nbsp; the manifestations of the numerous biomarkers associated with the asthmatic syndrome. The bioprocessed product was not toxic to leukemia cells, suggesting that it might be a safe product. The mouse assays demonstrate the potential value of the bioactive mushroom culture product as an anti-inflammatory and anti-allergic formulation that has the potential to prevent and/or treat allergic human diseases such as hay fever and asthma.</p><br /> <p>Dr. Friedman&rsquo;s group also investigated antimicrobial activities of red wine-based formulations containing plant extracts against <em>Escherichia coli</em> O157: H7 and <em>Salmonella enterica</em>.&nbsp; They evaluated the antimicrobial activities of three red wine based plant extract/plant essential oil (EO) formulations: olive extract powder/oregano EO, apple skin extract powder/lemongrass EO, and green tea extract powder/bitter almond EO, and their formula permutations against the foodborne pathogens Escherichia coli O157:H7 and <em>Salmonella enterica</em>. The formulations with oregano, lemongrass, or bitter almond EO inhibited the growth of both pathogens at acidic pH with bacterial loads of ~10⁴ or ~10⁹ bacteria/mL. At neutral pH, the formulations were less effective. Of the tested formulations, the lemongrass essential oil formulations, at pH 3.6, appeared to be the most effective against the tested pathogens, especially against Salmonella. The most active formulations merit evaluation for antimicrobial efficacy in liquid and solid food.</p><br /> <p>Dr. Mingruo Guo and colleagues (University of Vermont) investigated the effect of gamma radiation on the microbiological and physicochemical properties, protein-protein interaction and microstructure of whey proteins. Previous studies by the researchers have shown that whey protein structures can be modified by thermal and other chemical means to improve their functionality for use in value-added applications, such as wood and paper adhesives and stick glues. However, whey proteins can be aggregated and gelled prematurely when thermally treated and then stored at room temperature. Native protein structures in solutions and functional properties start to change when subjected to temperature up to 60&deg;C and irreversible changes occur at higher temperatures above 70&deg;C. Viscosity, turbidity, solubility, polymerization and other physicochemical changes of protein solutions can occur from the denaturation of whey proteins. The team treated samples of whey protein isolate (WPI) solutions (10-36% protein) with different dosages (10-35 KGy) of gamma radiation. They found that the lowest dosage (10 KGy) of gamma radiation used was sufficient to eliminate the presence of all viable microorganisms in WPI solutions and kept the samples sterilized for six months of shelf storage at room temperature. Control WPI solutions that did not received radiation treatment had 810 colonies forming units (cfu)/ml and 200 cfu/ml on total aerobic plate, and yeast &amp; molds plate counts, respectively. Brookfield viscosity was used to measure the effects of gamma radiation on polymerization of the WPI solutions. The researchers observed that viscosity of 27% protein solution was increased from 2.19 for the control to 4.78 mPa.s for the sample treated at 25 KGy, respectively, and viscosity also increased during storage at 23&deg;C. Overall, the significant increase in viscosity (mPa.s) of WPI solutions was most affected by the higher dosage of gamma radiation (15-25 KGy) and viscosity values also increased during the 6-month storage duration after treatment. Effects of gamma radiation and storage time on viscosity of whey protein solutions were significant (<em>P</em>&lt;0.05). Also, turbidity (measurement of opacity) of WPI solutions increased from 0.14 to 0.16 for untreated and treated samples (35 KGy), respectively. Soluble nitrogen content was also used to measure the effects of gamma radiation on polymerization of WPI solutions. The team found that nitrogen solubility decreased significantly from 100-54.7% in WPI solution samples treated at 35 KGy due to protein-based conformational modifications. Radiation treatment had significant impact on turbidity and soluble nitrogen content of whey protein solutions (<em>P</em>&lt;0.05). Polymerized interactions between whey proteins in solution were also analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Both 10 and 30% sample solutions showed that proteins were cross-linked in the samples treated by equal dosage of gamma radiation under the same amount of samples. Protein profiles suggested that non-quantitatively proteins were aggregated to higher molecular weights than samples untreated by gamma radiation. Also micrographs of TEM showed differences in protein-protein interactions induced by gamma radiation in treated WPI solutions, which displayed random and non-regular pattern protein structures. These affected structures seemed to be fragmented by gamma radiation and voids were created in the process. The researchers recommend additional research work to

Publications

<ol><br /> <li>Anderson, S. N., Richards, J. M., Esquer, H. J., <strong>Benninghoff, A. D.</strong>, Arif, A. M., and Berreau, L. M. (2015). A Structurally-Tunable 3-Hydroxyflavone Motif for Visible Light-Induced Carbon Monoxide-Releasing Molecules (CORMs). ChemistryOpen 4, 590-594.</li><br /> <li>Andrade, J. E., Ju, Y. H., Baker, C., Doerge, D. R., and <strong>Helferich, W. G.</strong> (2015). Long-term exposure to dietary sources of genistein induces estrogen-independence in the human breast cancer (MCF-7) xenograft model. Mol Nutr Food Res <strong>59</strong>, 413-423.</li><br /> <li>Andrade, J. E., Rosales, E., Lopez, J. R., Carrillo, E. P., Engeseth, N. J., and <strong>Helferich, W. G.</strong> (2015). Development of a point-of-use fortification technology for delivery of micronutrients in Honduras. J. Sci. Food Agric. <strong>95</strong>, 393-400.</li><br /> <li>Andruska, N. D., Zheng, X., Yang, X., Mao, C., Cherian, M. M., Mahapatra, L., <strong>Helferich, W. G.</strong>, and Shapiro, D. J. (2015). Estrogen receptor alpha inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression. Proc. Natl. Acad. Sci. U. S. A. <strong>112</strong>, 4737-4742.</li><br /> <li>Andruska, N., Zheng, X., Yang, X., <strong>Helferich, W. G.</strong>, and Shapiro, D. J. (2015). Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor alpha-positive breast cancer. Oncogene <strong>34</strong>, 3760-3769.</li><br /> <li>Atwell, L.L., Beaver, L.M., Shannon, J., <strong>Williams, D. E</strong>., Dashwood, R.H. and Ho, E. (2015) Epigenetic Regulation by Sulforaphane: Opportunities for Breast and Prostate Cancer Chemoprevention. Current Pharmacol. Reports. 1:102-111.</li><br /> <li>Atwell, L.L., Hsu, A., Wong, C.P., Stevens, J.F., Bella, D., Yu, T.., Pereira, C.B., L&ouml;hr, C.V., Christensen, J.M., Dashwood, R.H., <strong>Williams, D.E</strong>., Shannon, J. and Ho, E. (2014) Absorption and Chemopreventive Targets of Sulforaphane in Humans Following Consumption of Broccoli Sprouts or Myrosinase-Treated Broccoli Sprout Extracts. Molec. Nutr. Food Res. 59:424-433.</li><br /> <li>Aumsuwan, P., Khan, S. I., Khan, I. A., Avula, B., Walker, L. A., <strong>Helferich, W. G.</strong>, Katzenellenbogen, B. S., and Dasmahapatra, A. K. (2015). Evaluation of wild yam (Dioscorea villosa) root extract as a potential epigenetic agent in breast cancer cells. In Vitro Cell. Dev. Biol. Anim. <strong>51</strong>, 59-71.</li><br /> <li>Bates, M.A., Brandenberger, C., Langohr, I., Kumagai, K., Harkema, J.R., Holian, A., <strong>Pestka, J.J.,</strong> 2015. Silica Triggers inflammation and ectopic lymphoid neogenesis in the lungs in parallel with accelerated onset of systemic autoimmunity and glomerulonephritis in the lupus-prone NZBWF1 mouse. PLoS ONE 10, e0125481.</li><br /> <li><strong>Bello NT</strong> 2015 Clinical utility of guanfacine extended release in the treatment of ADHD in children and adolescents. Patient Prefer Adherence 9:877-885</li><br /> <li><strong>Bello NT</strong>, Walters AL, Verpeut JL, Caverly J 2014 Dietary-induced binge eating increases prefrontal cortex neural activation to restraint stress and increases binge food consumption following chronic guanfacine. Pharmacol Biochem Behav 125:21-28</li><br /> <li><strong>Bello NT</strong>, Yeh CY, Verpeut JL, Walters AL 2014 Binge-like eating attenuates nisoxetine feeding suppression, stress activation, and brain norepinephrine activity. PLoS One 9:e93610</li><br /> <li><strong>Benninghoff, A.D.</strong>, Lefevre, M., Hintze, K.J., Ward, R.E. and Broadbent, J.R. (2015)&nbsp; Fighting cancer with functional foods: new approaches to investigate the interactions of dietary bioactive chemicals and the gut microbiome.&nbsp; Journal of Developments in Sustainable Agriculture 10: 1-21.</li><br /> <li>Bittner, G.D., <strong>Denison, M.S.</strong>, Yang, C.S., Stoner, M.A. and He, G. (2014) Chemicals having estrogenic activity can be released from some bisphenol A-free, hard and clear, thermoplastic resins, Environ. Health 14 (1), 103.</li><br /> <li>Block, K. I., . . . . <strong>Helferich, W. G.</strong>, et al. (2015). Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin. Cancer Biol. 35 Suppl, S276-304.</li><br /> <li>Boonmuen, N., Gong, P., Ali, Z., Chittiboyina, A. G., Khan, I., Doerge, D. R., <strong>Helferich, W. G.</strong>, Carlson, K. E., Martin, T., Piyachaturawat, P., Katzenellenbogen, J. A., and Katzenellenbogen, B. S. (2015). Licorice root components in dietary supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic activities. Steroids.</li><br /> <li>Brennan, J. C., Bassal, A., He, G. and <strong>Denison, M.S.</strong> (2015) Development of a recombinant human ovarian (BG1) cell line containing estrogen receptor a and b for improved detection of estrogenic/antiestrogenic chemicals, Environ. Toxicol. Chem., In Press.</li><br /> <li>Brennan, J. C., He, G., Tsutsumi, T., Zhao, J., Wirth, E., Fulton, M. H. and <strong>Denison, M.S.</strong> (2015) Development of species-specific Ah receptor-responsive third generation CALUX cell lines with increased sensitivity and responsiveness, Environ. Sci. Tech. 49(19):11903-12.</li><br /> <li>Caron-Beaudoin, E., <strong>Denison, M. S.</strong> and Sanderson, J. T. (2015) Effects of neonicotinoids on promoter-specific expression and activity of aromatase in human adrenocortical carcinoma (H295R) and umbilical vein endothelial (HUVEC) cells, Toxicol. Sci., In Press.</li><br /> <li>Casey, S. C., Amedei, A., Aquilano, K., Azmi, A. S., Benencia, F., Bhakta, D., Bilsland, A. E., Boosani, C. S., Chen, S., Ciriolo, M. R., Crawford, S., Fujii, H., Georgakilas, A. G., Guha, G., Halicka, D., <strong>Helferich, W. G.</strong>, Heneberg, P., Honoki, K., Keith, W. N., Kerkar, S. P., Mohammed, S. I., Niccolai, E., Nowsheen, S., Vasantha Rupasinghe, H. P., Samadi, A., Singh, N., Talib, W. H., Venkateswaran, V., Whelan, R. L., Yang, X., and Felsher, D. W. (2015). Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin. Cancer Biol. <strong>35 Suppl</strong>, S199-223.</li><br /> <li>Chieng, M., Ying, S., Kunde, D., Cook, A., <strong>Nerurkar, P.V.,</strong> Ahuja, K. and Eri, R. Bitter melon extract protects against ER stress in LS174T colonic epithelial cells and copper-induced oxidation in human serum. Phytotherapy Research. Under revision, 2015</li><br /> <li>Chung, J., Anderson, S.A., Gwynn, B, Deck, K.M., Chen, M.J., Langer, N.B., Shaw, G.C., Huston, N.C., Boyer, L.F., Datta, S., Paradkar, P.N., Li, L., Wei, Z., Lambert, A.J., Sahr, K., Wittig, J.G., Chen, W., Lu, W., Galy, B., Schlaeger, T.M., Hentze, M.W., Ward, D.M., Kaplan, J., <strong>Eisenstein, R.S.</strong>, Peters, L.L., Paw, B.H. (2014) Iron regulatory protein 1 protects against mitoferrin-I deficient porphyria. J. Biol. Chem. 289:7835. PMC3953295.</li><br /> <li>Chung, J., Bauer, D.E., Ghamari, A., Nizzi, C.P., Deck, K.M., Kingsley, P.D., Yuen, Y.Y., Huston, N.C., Chen, C., Schultz, I.J., Dalton, A.J., Wittig, J.G., Palis, J., Orkin, S.H., Lodish, H.F., <strong>Eisenstein, R.S.</strong>, Cantor, A.B. and Paw, B.H. (2014) The mTORC/4E-BP pathway coordinately regulates hemoglobin production with L-leucine availability. Sci Signal. 2015 8(372):ra34. PMC4402725.</li><br /> <li><strong>Coulombe, R.A.</strong>, Bergeson, J., Aguilar, S., Hergert, N., and Lefevre, M. (2014) Effects of Ambient Particulate Air Pollution on Pulmonary Function, Pulmonary and Systemic Inflammation, and Lack Protective Effect of a Comprehensive Antioxidant and Anti-Inflammatory Dietary Supplement. PLOS One (in press).</li><br /> <li>Cox-York K, Sheflin AM, Foster MT, Gentile CL, Kahl A, Koch L, Britton S, <strong>Weir TL</strong> (2015) Gut ecology associated with high innate aerobic capacity protects against ovariectomy-induced cardiometabolic risk. Physiol Reports 3, e12488 .</li><br /> <li>Croes, K., Debaille, P., Van den Bril, B., Staelens, J., Vandermarken, T., Van Langenhove, K., <strong>Denison, M.S.</strong>, Leermakers, M. and Elskens, M. (2015) Assessment of estrogenic activity in PM₁₀ air samples with the ERE-CALUX bioassay: method optimization and implementation at an urban location in Flanders (Belgium), Chemosphere 144, 392-398.</li><br /> <li>Davis, A. P., <strong>Benninghoff, A. D.</strong>, Thomas, A. J., Sessions, B. R., and White, K. L. (2015). DNA methylation of the LIN28 pseudogene family. BMC Genomics 16, 287.</li><br /> <li>DeGroot, D.E., Franks, D.G., Higa, T., Tanaka, J., Hahn, M.E. and <strong>Denison, M.S.</strong> (2015) Naturally-occurring marine brominated indoles are aryl hydrocarbon receptor ligands/agonists, Chem. Res. Toxicol. 28, 1176-1185.</li><br /> <li>Ferguson, L. R., Chen, H., Collins, A. R., Connell, M., Damia, G., Dasgupta, S., Malhotra, M., Meeker, A. K., Amedei, A., Amin, A., Ashraf, S. S., Aquilano, K., Azmi, A. S., Bhakta, D., Bilsland, A., Boosani, C. S., Chen, S., Ciriolo, M. R., Fujii, H., Guha, G., Halicka, D., <strong>Helferich, W. G.</strong>, Keith, W. N., Mohammed, S. I., Niccolai, E., Yang, X., Honoki, K., Parslow, V. R., Prakash, S., Rezazadeh, S., Shackelford, R. E., Sidransky, D., Tran, P. T., Yang, E. S., and Maxwell, C. A. (2015). Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin. Cancer Biol. 35 Suppl, S5-S24.</li><br /> <li>Gentile CL, <strong>Weir TL</strong> , Cox-York K , Yuren W, Wang D, Reese L, Moran G, Estrada A, Mulligan C, Pagliassotti M, Foster MT (2014) The Role of Visceral and Subcutaneous Adipose Tissue Fatty Acid Composition in Liver Pathophysiology Associated with NALFD. Adipocyte, doi=10.4161/21623945.2014.978662</li><br /> <li>Hintze, K.J, Cox, J.E., Rompato, G., <strong>Benninghoff, A.D.</strong>, Ward, R.E., Broadbent, J., and Lefevre, M. (2014)&nbsp; Broad scope method for creating humanized animal models for animal health and disease research through antibiotic treatment and human fecal transfer.&nbsp; Gut Microbes 5(2): 1-9</li><br /> <li>Hong, M.Y., <strong>N.D. Turner</strong>, M.E. Murphy, R.J. Carroll, R.S. Chapkin, and J.R. Lupton.&nbsp; In vivo regulation of colon cell proliferation, differentiation, apoptosis and P27Kip1 by dietary fish oil and butyrate in rats.&nbsp; Cancer Prevention Research (In Press).</li><br /> <li>Jiang, W. G., Sanders, A. J., Katoh, M., Ungefroren, H., Gieseler, F., Prince, M., Thompson, S. K., Zollo, M., Spano, D., Dhawan, P., Sliva, D., Subbarayan, P. R., Sarkar, M., Honoki, K., Fujii, H., Georgakilas, A. G., Amedei, A., Niccolai, E., Amin, A., Ashraf, S. S., Ye, L., <strong>Helferich, W. G.</strong>, Yang, X., Boosani, C. S., Guha, G., Ciriolo, M. R., Aquilano, K., Chen, S., Azmi, A. S., Keith, W. N., Bilsland, A., Bhakta, D., Halicka, D., Nowsheen, S., Pantano, F., and Santini, D. (2015). Tissue invasion and metastasis: Molecular, biological and clinical perspectives. Semin. Cancer Biol. 35 Suppl, S244-275.</li><br /> <li>Johnson, N.B., Deck, K.M., Nizzi, C.P. and <strong>Eisenstein, R.S.</strong> Interrelationships Between Iron-Sulfur Cluster Biogenesis and Control of Iron Metabolism by Iron Regulatory Protein 1 and the E3 Ubiquitin Ligase FBXL5. In preparation.</li><br /> <li>Kang, Y., Nian, H., Rajendran, P., Kim, E., Dashwood, W.M., Pinto, J., Boardman, L., Thibodeau, S., Limburg, P., L&ouml;hr, C., Bisson, W., <strong>Williams, D</strong>.<strong>E.</strong>, Ho, E. and Dashwood, R.H. (2014) HDAC8 and STAT3 Repress BMF Gene Activity in Colon Cancer Cells. Cell Death Dis. 5:e1476.</li><br /> <li>Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, Wilson KE, Glover LE, Kominsky DJ, Magnuson AM, <strong>Weir TL</strong>, Ehrentraut SE, Nguyen V, Taylor CT, Colgan SP (2015) Host-Microbe Crosstalk between Short-Chain Fatty Acids and Intestinal Epithelial HIF Provides a New Mechanism to Augment Tissue Barrier Function. Cell Host &amp; Microbe DOI: <a href="http://dx.doi.org/10.1016/j.chom.2015.03.005">http://dx.doi.org/10.1016/j.chom.2015.03.005</a>.</li><br /> <li>Khedidji, S., Croes, K., Yassaa, N., Ladji, R., <strong>Denison, M.S.</strong>, Baeyens, W. and Elskens, M. (2015) Assessment of dioxin-like activity in PM₁₀ air samples from an industrial location in Algeria, using the DRE-CALUX bioassay, Environ. Sci. Poll. Res., In Press.</li><br /> <li>Kim, E., Bisson ,W.H., L&ouml;hr, C.V., <strong>Williams, D.E</strong>., Ho, E., Dashwood, R.H. and Rajendran, P. (2015) Histone and Non-Histone Targets of Dietary Deacethylase Inhibitors. Curr. Topics Med. Chem., in press.</li><br /> <li>Kim, E., L.A. Davidson, R.S. Zoh, B.S. Patil, G.K. Jayaprakasha, E.S. Callaway, C.D. Allred, <strong>N.D. Turner</strong>, and R.S. Chapkin.&nbsp; Homeostatic responses of colonic LGR5 stem cells following acute in vivo exposure to a genotoxic carcinogen.&nbsp; Carcinogenesis (Accepted with revision).</li><br /> <li>Liu, Y., Hilakivi-Clarke, L., Zhang, Y., Wang, X., Pan, Y. X., Xuan, J., Fleck, S. C., Doerge, D. R., and <strong>Helferich, W. G.</strong> (2015). Isoflavones in soy flour diet have different effects on whole-genome expression patterns than purified isoflavone mix in human MCF-7 breast tumors in ovariectomized athymic nude mice. Mol Nutr Food Res <strong>59</strong>, 1419-1430.</li><br /> <li>Maayah, Z.H., Ghebeh, H.B., Alhaider, A.A., El-Kadi, A.O., Soshilov, A.A., <strong>Denison, M.S.</strong>, Ansari, M.A. and Korashy, H.M. (2015) Metformin inhibits 2,7-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway, Toxicol. Appl. Pharmacol. 284, 217-226.&nbsp;</li><br /> <li>Madak-Erdogan, Z., Gong, P., Zhao, Y. C., Xu, L., Wrobel, K. U., Hartman, J. A., Wang, M., Cam, A., Iwaniec, U. T., Turner, R. T., Twaddle, N. C., Doerge, D. R., Khan, I. A., Katzenellenbogen, J. A., Katzenellenbogen, B. S., and <strong>Helferich, W. G.</strong> (2015). Dietary licorice root supplementation reduces diet-induced weight gain, lipid deposition, and hepatic steatosis in ovariectomized mice without stimulating reproductive tissues and mammary gland. Mol Nutr Food Res.</li><br /> <li>Madeen, E., Corley, R.A., Crowell, S., Turteltaub, K., Ognibene, T., Malafatti, M., McQuistan, T.J., Garrard, M., Sudakin, D. and <strong>Williams, D.E. </strong>(2014) Human In Vivo Pharmacokinetics of [¹⁴C]Dibenzo[def,p]chrysene by Accelerator Mass Spectrometry Following Oral</li><br /> <li>Mexia, N., Gaitanis, G., Velegraki, A., Soshilov, A., <strong>Denison, M.S.</strong> and Magiatis, P. (2015) Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast, Arch. Biochem. Biophys. 571, 16-20.</li><br /> <li>Mohammad, R. M., Muqbil, I., Lowe, L., Yedjou, C., Hsu, H. Y., Lin, L. T., Siegelin, M. D., Fimognari, C., Kumar, N. B., Dou, Q. P., Yang, H., Samadi, A. K., Russo, G. L., Spagnuolo, C., Ray, S. K., Chakrabarti, M., Morre, J. D., Coley, H. M., Honoki, K., Fujii, H., Georgakilas, A. G., Amedei, A., Niccolai, E., Amin, A., Ashraf, S. S., <strong>Helferich, W. G.</strong>, Yang, X., Boosani, C. 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Impact Statements

1. W3122 researchers have successfully conducted a clinical trial involving micro-dosing PAHs to humans in order to characterize the pharmacokinetics at levels found in food. They also performed genome-wide analysis of PAH-induced alteration in the offspring transcriptome (mRNA), methylome (DNA methylation) and epigenome (miRNA, ncRNA) following maternal exposure and amelioration by I3C and SFN. For more information, contact David Williams (david.williams@oregonstate.edu).

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Participants

Brief Summary of Minutes

The 2016 Annual Meeting of the W-3122 Multistate Group was called to order by the Chair, Dr. Nancy Turner on the morning of October 6. Dr. Mike Harrington (WAAESD) provided an overview of the status of the multi-state program, the current funding priorities identified in the NIFA strategic plan, and budget status at NIFA. Last year, this group was recognized with the Western Region Award of Excellence in Multistate Research. Dr. Harrington would like to resubmit a nomination for W3122 to be considered for the national award again this year. Each member present delivered a presentation to update the group on his/her progress (content summarized in the Annual Group Report). At the business meeting, new officers for 2016-2017 were selected: Chair, Meijun Zhu; Vice-Chair, Yuhua Farnell; and Secretary, Susan Tilton. Also, the dates for the 2017 annual meeting will be October 4-6 and the meeting will be held in Calistoga, CA.

Reports submitted, but not able to attend annual meeting

Benninghoff, Abby, abby.benninghoff@usu.edu (Utah State University)

Denison, Michael, msdenison@ucdavis.edu (University of California, Davis)

Eisenstein, Richard, eisenste@nutrisci.wisc.edu (University of Wisconsin-Madison)

Friedman, Mendel, friedman@ars.usda.gov (USDA-ARS Albany)

Nerurkar, Pratibha, pratibha@hawaii.edu (University of Hawaii)

Pagliarini, David, pagliarini@morgridge.org (Morgridge Institute for Research)

Pestka, Jim, pestka@msu.edu (Michigan State University)

Ricketts, Marie-Louise, mricketts@cabnr.unr.edu (University of Nevada, Reno)

Romagnolo, Donato, donato@u.arizona.edu (University of Arizona)

Weir, Tiffany, tiffany.weir@colostate.edu (Colorado State University)

 

Accomplishments

<p><strong>OBJECTIVE 1: Determine the mechanisms by which dietary bioactive compounds protect against human diseases.</strong></p><br /> <p><strong>&nbsp;</strong></p><br /> <p><span style="text-decoration: underline;">Dr. Mendel Friedman (USDA-ARS Albany)</span></p><br /> <p>Dr. Mendel Friedman and colleagues have demonstrated that combinations of shiitake mushroom (<em>Lentinus edodes</em>) mycelia with other sources of bioactive compounds, such as fermented elm tree (<em>Ulmus parvifolia</em>) bark extract or turmeric are protective against several disease states. In the first study, they found the combination of elm tree bark extract and the shiitake mushroom mycelia culture resulted in anti-inflammatory and anti-allergic actions in a mouse model of allergic asthma. In the second study, they found the combination of turmeric and the shiitake mushroom mycelia culture protected mice against both liver damage (necrosis) and lethality induced by <em>Salmonella </em>Typhimurium. The protection was induced by stimulation of the immune system.</p><br /> <p><span style="text-decoration: underline;">&nbsp;</span></p><br /> <p><span style="text-decoration: underline;">Dr. Roger Coulombe (Utah State University)</span></p><br /> <p>Dr. Roger Coulombe and colleagues have developed an avian embryo exposure model that reduces use of live animals in research, and allows them to study the molecular mechanisms of regulatory pathways of the universal detoxifying enzyme glutathione S-transferases. Previous results from our laboratory have demonstrated that domesticated turkeys (Meleagris gallopavo) are especially sensitive to aflatoxicosis, while Eastern wild turkeys (M. g. silvestris) are relatively resistant. In ovo exposure provided a controlled AFB1 challenge and comparison of domesticated and wild turkeys. Gene expression responses to AFB1 in the embryonic hepatic transcriptome were examined using RNA-sequencing (RNA-seq). Eggs were injected with AFB1 (1 g) or sham control and dissected for liver tissue after 1 day or 5 days of exposure. Libraries from domesticated turkey (n = 24) and wild turkey (n = 15) produced 89.2 Gb of sequence. Approximately 670 M reads were mapped to a turkey gene set. Differential expression analysis identified 1535 significant genes with |log2 fold change| &gt; 1.0 in at least one pair-wise comparison. AFB1 effects were dependent on exposure time and turkey type, occurred more rapidly in domesticated turkeys, and led to notable up-regulation in cell cycle regulators, NRF2-mediated response genes and coagulation factors. Further investigation of NRF2-response genes may identify targets to improve poultry resistance.</p><br /> <p>Changes in methylation, particularly at CpG sites clustered in the promoter region of a gene, can lead to changes in expression. To identify whether methylation differences may be responsible for GST silencing in domesticated turkeys, Dr. Coulombe&rsquo;s group searched for CpG islands "upstream" of the 5' end GSTA genes. CpG sites in the GSTA region occur less frequently than expected by chance, with apparent CpG islands near the 5' ends of most of the GSTA genes, but not GSTA3--the one we are most interested in. The SNPs that have been identified in this region between wild and domestic turkeys do not affect the number of CpG sites, so it doesn't appear that a CpG island which was present in wild turkeys has been lost in domestic turkeys.</p><br /> <p>Genes may share promoters, so we are examining the CpG island in the promoter of GSTA4 (the next gene upstream from GSTA3). The Coulombe lab has designed primers to amplify the GSTA4 promoter region and will be using a methylation sensitive restriction enzyme-based method to determine whether the CpG sites are differentially methylated between Wild and Domestic turkeys.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Abby Benninghoff (Utah State University)</span></p><br /> <p>Dr. Benninghoff&rsquo;s group reported preliminary results from an ongoing multi-generation&nbsp;mouse study designed&nbsp;to determine the impact of ancestral or multi-generational consumption of the total Western diet (TWD), a Western-style diet formulated for rodents using human US nutrient intake data, in a murine model of inflammation-associated colorectal carcinogenesis.&nbsp; C57BL/6J mice were bred for three generations, during which they were fed an optimized diet (AIN93G), TWD or a simple high fat diet (45% DIO) in the F₀ only, F₀ through F₃, or the F₃&nbsp;generation only. &nbsp;The azoxymethane and dextran sodium sulfate model of inflammation-associated CRC was employed in the F₃ offspring.&nbsp; Notably, ancestral exposure (F₀ generation) to the TWD markedly enhanced CRC incidence and disease severity as measured by tumor multiplicity and burden in&nbsp;F₃&nbsp;offspring (P&lt;0.05), whereas the DIO diet had little effect on colon tumorigenesis (P&gt;0.05).&nbsp; Moreover, cumulative exposure to TWD over multiple generations had an even stronger effect on CRC severity compared to F₃ offspring provided TWD directly (P&lt;0.05). &nbsp;Ancestral exposure to either TWD or DIO diet did not appear to markedly alter body weight or composition in&nbsp;F₃&nbsp;offspring (P&gt;0.05).&nbsp; These data suggest that ancestral exposure to a Western-style diet may be as detrimental as direct exposure in regards to colon tumorigenesis. &nbsp;Also, as part of this study, another cohort of&nbsp;F₃&nbsp;mice were provided drinking water supplemented with green tea extract, with the objective to determine how ancestral patterns of exposure to the Western diet impacted the efficacy of green tea as an anticancer agent. &nbsp;Analyses of outcomes from this arm of the study are ongoing.</p><br /> <p>Previously, Dr. Benninghoff&rsquo;s research group (USU) reported that dietary supplementation with tart&nbsp;cherries&nbsp;caused a significant 40% reduction in tumor incidence in mice fed AIN93G, whereas tart cherries had no effect on tumor incidence in mice fed TWD. &nbsp;However, tart cherry powder supplementation did not&nbsp;significantly affect tumor multiplicity, tumor size or colitis in mice fed either basal diet. In ongoing analysis of this work, her group examined the impact of TWD and tart cherry supplementation on colon inflammation. &nbsp;The azoxymethane and dextran sodium sulfate (DSS) model of inflammation-associated CRC was employed, which triggers colitis within 10 days of DSS treatment.&nbsp;&nbsp;Disease activity, colon tissue histopathology and biomarkers of inflammation (immunohistochemistry) were assessed at multiple time points, including colitis, recovery and at the study end. Mice fed TWD experienced significantly elevated levels of inflammation and mucosal injury during the colitis phase, as compared to mice fed AIN93G, and this elevated response was evident throughout recovery and progression to tumorigenesis.&nbsp;&nbsp;However, treatment with tart cherry did not significantly affect inflammation or mucosal injury. &nbsp;Thus, the anticancer activity of tart cherry is likely not related to changes in colonic inflammation.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Marie-Louise Ricketts (University of Nevada, Reno)</span></p><br /> <p>In an effort to determine the potential use of a grape seed procyanidin extract (GSPE) as a natural therapy to treat or ameliorate metabolic disorders, Dr. Ricketts and colleagues have conducted several <em>in vit</em>ro and <em>in vivo </em>studies, in order to further elucidate its&rsquo; molecular mechanism of action. To date our investigations have led to the following findings:</p><br /> <p><em><span style="text-decoration: underline;">GSPE exerts a triglyceride-lowering effect in a hyperlipidemic state</span></em></p><br /> <p>In this study, rats were fed either a starch control diet or a diet containing 65% fructose for 8 weeks to induce hypertriglyceridemia. During the 9th week of the study, rats were maintained on their respective diet and administered vehicle (water) or GSPE via oral gavage for 7 days. Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control. GSPE administration in the fructose-fed rats attenuated this effect, resulting in a 41% decrease. GSPE inhibited hepatic lipogenesis via down-regulation of several genes including, sterol regulatory element binding protein 1c (<em>Srebp1c</em>) and stearoyl-CoA desaturase 1 (<em>Scd-1</em>) in the fructose-fed animals. GSPE increased fecal bile acid and total lipid excretion, decreased serum bile acid levels and increased the expression of genes involved in hepatic cholesterol synthesis. However, hepatic bile acid biosynthetic gene expression was not increased in the presence of GSPE and fructose. Serum cholesterol levels remained constant, while hepatic cholesterol levels decreased. GSPE did not modulate expression of genes responsible for esterification or biliary export of the newly synthesized cholesterol, but did increase fecal cholesterol excretion, suggesting that in the presence of GSPE and fructose, the liver may secrete more free cholesterol into the plasma, which may then be shunted to the proximal small intestine for direct basolateral to apical secretion and subsequent fecal excretion. The results from this study demonstrate that GSPE effectively lowers serum triglyceride levels in fructose-fed rats after one-week administration. This study provides novel insight into the mechanistic actions of GSPE in treating hypertriglyceridemia and demonstrates that it targets hepatic <em>de novo </em>lipogenesis, bile acid homeostasis and non-biliary cholesterol excretion as important mechanisms for reducing hypertriglyceridemia and hepatic lipid accumulation in the presence of fructose, a highly lipogenic dietary component.</p><br /> <p>&nbsp;</p><br /> <p><em><span style="text-decoration: underline;">Dietary procyanidins alter enterohepatic bile acid recirculation: elucidation of a novel mechanism to reduce triglyceridemia</span></em></p><br /> <p>Understanding the molecular basis by which dietary procyanidins modulate triglyceride and cholesterol homeostasis has important implications for the use of natural products in the treatment and prevention of cardiovascular disease. To determine whether modulation of bile acid homeostasis contributes to the hypotriglyceridemic action of GSPE, the effect on genes regulating bile acid absorption, transport and synthesis was examined <em>in vitro</em>, in Caco-2 cells, and <em>in vivo</em>, in wild type (C57BL/6) and farnesoid x receptor knockout (<em>Fxr</em>-/-) mice. Results from this study provide novel evidence demonstrating that GSPE is a naturally occurring gene-selective bile acid receptor modulator (BARM). Mechanistically, GSPE down-regulates genes involved in intestinal bile acid absorption and transport in an FXR-dependent manner, resulting in decreased enterohepatic bile acid recirculation. This correlates with increased fecal bile output, decreased serum triglyceride and cholesterol levels, increased hepatic cholesterol 7&alpha;-hydroxylase (Cyp7a1), and decreased intestinal fibroblast growth factor 15 (<em>Fgf15</em>) expression. GSPE also increased hepatic HmgCoA reductase (<em>Hmgcr</em>) and synthase (<em>Hmgcs1</em>) expression, while concomitantly decreasing sterol regulatory element-binding protein 1c (<em>Srebp1c</em>). GSPE selectively regulates intestinal FXR-target gene expression <em>in vivo</em>, and modulation of bile acid absorption and transport is a critical regulatory point for the consequential hypotriglyceridemic effects of GSPE.</p><br /> <p>&nbsp;</p><br /> <p><em><span style="text-decoration: underline;">GSPE exerts complementary effects with respect to triglyceride-lowering when administrated in conjunction with the bile acid sequestrant, cholestyramine</span></em></p><br /> <p>Bile acid sequestrants are lipid-lowering agents, which may be prescribed as a monotherapy or combination therapy to reduce the risk of coronary artery disease. Over 33% of adults in the United States use complementary and alternative medicine strategies, and we recently reported that grape seed procyanidin extract (GSPE) reduces enterohepatic BA recirculation as a means to reduce serum triglyceride levels. This study was designed to assess the effects on bile acid, cholesterol and triglyceride homeostatic gene expression following co-administration with GSPE and the bile acid sequestrant, cholestyramine (CHY). Eight-week old male C57BL/6 mice were treated for 4 weeks with either a control or 2% CHY-supplemented diet, after which, they were administered vehicle (water) or GSPE for 14 hours. Liver and intestines were harvested and gene expression was analyzed. Bile acid, cholesterol, non-esterified fatty acid and triglyceride levels were also analyzed in serum and feces. Results revealed that GSPE treatment alone, and co-administration with CHY, regulates bile acid, cholesterol and triglyceride metabolism differently than CHY administration alone. Notably, GSPE decreased intestinal apical sodium-dependent bile acid transporter (<em>Asbt</em>) gene expression, while CHY significantly induced expression. Administration with GSPE or CHY robustly induced hepatic bile acid biosynthetic gene expression, especially cholesterol 7&alpha;-hydroxylase (Cyp7a1), compared to control, while co-administration further enhanced expression. Treatment with CHY induced intestinal and hepatic cholesterologenic gene expression, while co-administration with GSPE attenuated the CHY-induced increase in the liver but not intestine. CHY also induced hepatic lipogenic gene expression, which was attenuated by co-administration with GSPE. Consequently, a 25% decrease in serum triglyceride levels was observed in the CHY+GSPE group, compared to the CHY group. Collectively, this study presents novel evidence demonstrating that GSPE provides additive and complementary efficacy as a lipid-lowering combination therapy in conjunction with CHY by attenuating hepatic cholesterol synthesis, enhancing bile acid biosynthesis and decreasing lipogenesis, warranting further investigation.</p><br /> <p>&nbsp;</p><br /> <p><em><span style="text-decoration: underline;">GSPE inhibits HDAC activity leading to increased Ppar&alpha; phosphorylation and target-gene expression to increase fatty acid &szlig;-oxidation</span></em></p><br /> <p>Histone deacetylases (HDACs) have emerged as epigenetic regulators of risk factors associated with the metabolic syndrome (MetS), and certain botanical extracts have proven to be potent HDAC inhibitors. Understanding the role of dietary procyanidins in HDAC inhibition is important in exploring the therapeutic potential of natural products. In this particular study, C57BL/6 mice were gavaged with vehicle (water) or grape seed procyanidin extract (GSPE, 250 mg/kg) and terminated 14 h later. Liver and serum were harvested to assess the effect of GSPE on HDAC activity, histone acetylation, Ppar&alpha; activity and target-gene expression, and serum lipid levels. Results show that GSPE increased histone acetylation and decreased Class I HDAC activity <em>in vi</em>vo, and dose-dependently inhibited recombinant HDAC2 and 3 activities <em>in vitro</em>. Accordingly, Ppar&alpha; gene and phosphorylated protein expression were increased, as were target genes involved in fatty acid catabolism, suggesting increased Ppar&alpha; activity. Serum fibroblast growth factor 21 (Fgf21) was elevated, and triglyceride levels were reduced by 28%. This study revealed that mechanistically GSPE regulates HDAC and Ppar&alpha; activities to modulate lipid catabolism and reduce serum triglycerides <em>in vivo</em>.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Pratibha Nerurkar (University of Hawaii)</span></p><br /> <p>In Hawaii, minority populations such as Native Hawaiians and Pacific Islanders (NHPI) have more than twice the rate of obesity-associated type 2 diabetes (T2D) as Caucasians, and are more than five times as likely to die from T2D. Current therapies for obesity are complicated due to factors including an inability to maintain long-term weight loss and drug-drug interactions. In addition, conventional therapies may not be affordable, suitable and/or acceptable for culturally sensitive minority populations. There is a growing awareness and mounting body of scientific evidence, that successful implementation of strategies to control T2D among ethnic minorities will require culturally appropriate interventions.</p><br /> <p>Dr. Pratibha Nerurkar and colleagues have demonstrated that laboratory-prepared juice (fNJ) improves not only glucose and lipid metabolism, but also prevents weight gain in mice fed high fat diet (HFD, 58% fat). Although the worldwide market for noni products are currently estimated at $2 billion and laboratory-based research has supported health claims of noni, clinical studies supporting health benefits of noni are scant and limited to Tahitian noni juice. We compared the anti-diabetic and anti-inflammatory effects of fNJ and commercial noni juices, differences in chemical metabolites and modulation of gut microbiome. Our findings indicate that laboratory-based fNJ was more potent at improving glucose metabolism and inflammation within four weeks of starting treatment of HFD-fed mice. These effects are possibly associated with differences in the chemical composition of commercial and laboratory-prepared juices, as determined by metabolomics studies.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. James Pestka (Michigan State University)</span></p><br /> <p>Lupus is a debilitating autoimmune disease that adversely affects 1.5 million Americans. While the genome is a primary predisposing factor for autoimmunity, lifetime environmental exposures to factors (i.e., exposome) such as environmental toxicants and diet are now recognized to modulate hereditary effects. Experimental animal and epidemiological studies have linked exposure to the respiratory toxicant silica to lupus and other autoimmune diseases. Importantly, nearly 2 million Americans are occupationally exposed to respirable silica. In contrast, both animal and clinical studies suggest that consumption of DHA and other &omega;-3 PUFAs can both prevent and resolve inflammation and autoimmune nephritis. Little is known about how respiratory toxicants like silica trigger lupus or how DHA supplementation could be harnessed to block environmental triggering. This critical barrier results in unnecessary lupus burden in genetically predisposed people that are exposed to respiratory toxicants. Lupus onset/progression in such individuals could potentially be mitigated by development and implementation of effective, low cost prophylactic approaches employing optimized supplementation with &omega;-3 PUFAs, already regularly consumed by over 20 million Americans. Research in the Pestka lab focuses on using such an approach to prevent lupus. Taken together, our research team now has a model that enables dissection of the countervailing roles of silica (potentiation) and DHA (attenuation) in lupus initiation.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Nancy Turner (Texas A&amp;M University)</span></p><br /> <p>Colon cancer and inflammatory bowel disease are major contributors to morbidity and mortality in the US, and dietary patterns have been suggested to be responsible for a large fraction of the cases. Recent evidence demonstrates diet may influence these diseases through its impact upon the microbiota. We are exploring the impact of dietary fiber sources, particularly those with unique or high levels of phenolic compounds on colon health.</p><br /> <p>In our first experiment, we determined if polyphenol-rich sorghum brans would influence the colon microbiota of healthy rats. The experimental diets included a sorghum bran that contained either condensed tannins, deoxyanthocyanins or a combination of the two. Within four weeks of changing from a standard pelleted diet to the semi-purified experimental diets (devoid of phenolic molecules), rats consuming cellulose as the fiber source had an elevated proportion of <em>Firmicutes</em> and a dramatic reduced proportion of <em>Bacteroidetes</em>. In contrast, rats consuming a diet containing condensed tannins had reduced <em>Firmicutes</em> and elevated <em>Bacteroidetes</em>. Those consuming a diet containing either diet with deoxyanthocyanins maintained relatively similar proportions of these microbial phyla. These data demonstrate that diets low/depleted of polyphenols induces greatly elevated ratios of <em>Firmicutes</em>/<em>Bacteroidetes</em>, a pattern similar to that found in obese individuals or those with inflammatory bowel disease. Importantly, it was possible to protect against this shift by including a single, polyphenol-rich fiber source.</p><br /> <p>Our second project explored the impact of dried plums on colon cancer, where we found a 50% reduction in early colon lesions in rats consuming a diet containing dried plums. There were changes in the distal colon microbiota of carcinogen-injected rats consuming the control diet. However, the dried plum diet produced minimal changes in microbiota between the proximal and distal colon, and the changes in microbiota induced by the carcinogen were not as prominent in the dried plum group. We are performing untargeted metabolomics analyses on feces to determine if the changes in microbiota resulted in altered metabolite profiles. We discovered several compounds endogenous to plums in the luminal contents (both proximal and distal), with several of those compounds being demonstrated in the existing literature to suppress proliferation and enhance apoptosis in colon cancer cells. In addition, there were multiple compounds produced from microbial metabolism of phenolic molecules identified in the luminal contents from the proximal and distal colon of rats provided the plum diet. These molecules have also been demonstrated to protect against carcinogenesis. Additional experiments using dried plums, or compounds isolated from plums have demonstrated effects on bone, as well as colon cancer, demonstrating the potential for systemic benefits of dried plum consumption.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Tiffany Weir (Colorado State University)</span></p><br /> <p>Colorectal cancer is one of the major causes of cancer deaths, but the majority of cases can be prevented by modification of lifestyle factors such as diet. In particular, fiber intake has been associated with a decreased risk of developing colorectal cancer. Recently, several lines of evidence have suggested roles for the gut microbiota in development and progression of colorectal cancers, and dietary fiber is an important modulator of gut bacterial populations. We are testing the hypothesis that dietary intervention using two sources dietary fiber, stabilized rice bran (SRB) and navy bean powder (NBP), will modulate the gut microbiota and improve the intestinal environment for reduced risk of colorectal cancer. Toward this goal, we have identified specific microbial (and metabolite) changes associated with increased intake of either SRB or NBP in healthy cohorts with and without a history of colorectal cancer. Because human-associated microbiota responded differently between SRB and NBP treatment groups, ongoing research is aimed at specifically examining the different fiber composition of these foods alters their interactions with the microbiota. Specifically, we are exploring the interaction between arabinoxylans from SRB and how they interact with mucin-degrading bacteria such as <em>Bacteroides ovatus</em> and <em>Akkermansia muciniphila</em>.</p><br /> <p>High fruit and vegetable (F&amp;V) consumption is also associated with protection against CRC as well as a number of other diseases. However, this protective effect cannot be explained by increased fiber intake alone and is likely due to the myriad phytochemicals present in these foods. To better understand how F&amp;V consumption mechanistically affects host physiology for improved health outcomes, biomarkers of F&amp;V intake are needed. To this end, we are exploring various metabolomic profiling strategies to identify chemical signatures associated with varying levels of F&amp;V intake. Completed analysis of urine samples from a controlled F&amp;V feeding study indicate that there are multiple metabolites associated with either high or low F&amp;V intake, including many phytochemicals specific to particular botanical families (i.e., sulforaphane and capsaicin), as well as several host derived metabolites (such as sialic acid-the terminal molecule in intestinal mucins), which may serve as indicators of host health. Future studies will be directed at exploring ionomics platforms for signature generation as well as validating the biomarker signatures that have already been identified using a larger study population.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Richard Eisenstein (University of Wisconsin, Madison)</span></p><br /> <p>First, we are investigating the extent to which the pathologies associated with obesity and iron overload may partly act through similar signaling pathways. We are interested in understanding the basis of the mild anemia observed in obesity and the role of the so-called unfolded protein response (UPR) and signaling pathways down-stream of the UPR that may modulate production of the iron regulatory protein hepcidin. Evidence in the literature indicates that hepcidin expression is activated by the UPR. Activation of the UPR in obese subjects could stimulate hepcidin production, which is predicted to reduce dietary iron absorption and iron recycling leading to anemia. A final component of this work is to examine if expression of the transcription factor HIF2-alpha is altered in obese mice. HIF2alpha expression is controlled at the translational level by iron and we hypothesize a role for the UPR. Part of our work here focuses on defining the role of translational regulatory elements in the 5&rsquo; untranslated region of the HIF2alpha mRNA using a luciferase reporter assay.</p><br /> <p>Second, we are examining how the iron regulated RNA binding protein, iron regulatory protein 1 (IRP1), controls dietary iron absorption and erythropoiesis during fetal and postnatal development. An ultimate goal of this, and a subject of our recently submitted Hatch renewal proposal, is whether dietary factors known to control HIF2alpha expression might consequently control dietary iron absorption. IRP1 is the key iron mediator of HIF2alpha mRNA translation. IRP1 is a repressor of HIF2alpha synthesis and loss of IRP1 translationally activates HIF2alpha mRNA. HIF2alpha is a transcriptional activator of the main blood forming hormone erythropoietin and also the iron transport system controlling dietary iron acquisition in the duodenum. Mice lacking IRP1 develop a severe but transient polycythemia (too many red cells) and absorb more iron to promote red cell overproduction. We have recently found that these mice have very strongly repressed hepcidin mRNA at birth and our data obtained over the past year suggests that this does <span style="text-decoration: underline;">not</span> involve canonical mechanisms for controlling hepcidin gene transcription. Furthermore, our studies over the past year indicate that IRP1 is an important factor controlling placental iron transfer from the mother to the fetus. We are currently writing a paper on this work.</p><br /> <p>Third, we have further examined the role of IRP1 in controlling HIF2alpha and erythropoiesis by using a zinc-finger nuclease to delete the iron responsive element (IRE) in HIF2alpha mRNA so that IRP1 cannot control translation of this message. Mice lacking the IRE in HIF2alpha display a dysregulation of erythropoiesis that appears milder, in some respects, than in mice lacking IRP1. We are focusing on what additional mechanisms may be dysregulated in mice lacking IRP1 vs. those lacking the IRE in HIF2alpha mRNA.</p><br /> <p>Fourth, we are examining the iron-dependent mechanisms controlling IRP1 function as a means to understand how dietary iron absorption is controlled in disease states including iron deficiency as well as in inflammatory disorders. This includes the known impact of inflammatory scenarios in reducing intestinal iron absorption. The ability of IRP1 to bind mRNA is determined by insertion or loss of an Fe-S cluster with the cluster-free apoprotein form binding RNA. A second mechanism involves iron-dependent degradation of the IRP1 apoprotein. To better understand how dietary iron absorption is controlled we are focusing on the ability of IRP1 to be regulated by the Fe-S cluster vs. the protein degradation mechanism. A manuscript on this work will be submitted in November 2016.</p><br /> <p>Fifth, our expertise on the regulation of function of IRP1 and iron metabolism in general has allowed us to collaborate with other labs study the control of cellular iron metabolism including the lack of impact of pharmacological agents on IRP1.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. David Pagliarini (University of Wisconsin, Madison)</span></p><br /> <p>We have continued to investigate the effects of iron deprivation on the cellular control of mitochondrial biogenesis. Using microarray and quantitative mass-spectrometry approaches, we discovered that depriving C2C12 mouse myotubes of iron, through treatment with the iron chelator deferoxamine (DFO) leads to a global decrease in the transcript abundance of mitochondrial- and nuclear-encoded mitochondrial genes and mitochondrial proteins. We have found that this response to iron chelation is universal across a broad range of cell types, rapid (occurring within 24 hours) and dose-dependent. We also found that the effect of iron chelation on transcript levels is fully reversed with (histone deacetylase) HDAC inhibition, consistent with histone post-translational modification (PTM)-mediated regulation of gene expression. To buttress our observations on the role of histone-PTMs in the iron deprivation induced transcriptional regulation of mitochondrial biogenesis, we performed additional transcript labeling and ChIP-qPCR analyses. First, to test whether the change in acetylation is simply a general decrease found at all genes regardless of their expression, we added the mitochondrial non-OxPhos encoding gene <em>Vdac1</em>, whose transcript levels are not affect by iron chelation. We found that there is no change in <em>Vdac1</em> transcript degradation, and we observed decreases in the synthesis of <em>Vdac1</em> at the final two time points of our time-course, which occurred after the changes in OxPhos transcripts. We also only observed relatively small (and no statistically significant) changes in histone acetylation and no change in histone methylation at <em>Vdac1</em> consistent with the lack of change in <em>Vdac1</em> expression in response to iron chelation. We also added non-mitochondrial genes to our analyses, including <em>Hk2</em> and <em>Slc2a1 </em>(both involved in glucose metabolism). We found that their transcription increases in response to DFO, and we also find that DFO increases their stability, suggesting that regulation at both levels (synthesis and degradation) contributes to the overall increase in their total transcript abundance. Our ChIP-qPCR analysis shown that iron deprivation causes no significant change in histone acetylation (or methylation) at either gene, suggesting that the loss of acetylation is specific to certain genes rather than genome-wide. Second, we added more mitochondrial OxPhos-encoding genes to our ChIP-qPCR analyses, including <em>Ndufs8</em> and <em>Cycs</em>, and found that their histone-PTM profiles are consistent with the previously analyzed OxPhos-encoding genes.</p><br /> <p>Next, as we observed a general increase in methylation following iron deprivation, we used the demethylase inhibitor dimethyloxalylglycine (DMOG) to test if a decrease in histone demethylase activity is sufficient to cause a similar mitochondrial response. Most lysine demethylase reactions are catalyzed by the Jumonji C (JmjC)-domain containing demethlyases that require &alpha;-ketoglutarate, O₂ and Fe²⁺. These JmjC demethylases can be inhibited by a-ketoglutarate analogs, such as DMOG, without affecting iron levels. Interestingly, we found that DMOG did not affect OxPhos-encoding transcripts, suggesting that methylation is not the main regulator of the mitochondrial transcriptional response to iron deprivation. Finally, we published these recent discoveries on iron deprivation-induced, histone-PTM transcriptional regulation of mitochondrial biogenesis in the 2016 September 30 issue of the Journal of Biological Chemistry.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Meijun Zhu (Washington State University)</span></p><br /> <p>Beyond their nutritional impact on colonic epithelial cells, the intestinal microbiota metabolite butyrate has been shown to exert beneficial effects on intestinal homeostasis and metabolism. Mast cells are well known for their roles in mediating allergy responses and regulating gut inflammation. We demonstrate that butyrate profoundly inhibited proliferation of mouse mastocytoma P815 cells through inducing cell cycle arrest and apoptosis, as well as decreasing c-Kit activation; butyrate also increased early and late stage apoptotic P815 cells. Additionally, butyrate suppressed FceRI-dependent cytokine production in murine primary BMMC, which are likely mediated by inhibition of histone deacetylation.</p><br /> <p>Goji berry is a traditional Chinese tonic food. Dietary goji berry ameliorated DSS-induced body weight loss, diminished diarrhea and gross bleeding, resulted in a significantly decreased disease activity index, as well as DSS associated colon shortening. Histologically, it ameliorated mucosal damage and neutrophil infiltration into colonic intestinal tissue in response to DSS challenge, which was associated with decreased expression of chemokine (C-X-C motif) ligand 1 (CXCL1) and monocyte chemoattractant protein-1 (MCP-1), as well as inflammatory mediators, interleukin-6 and cyclooxygenase-2. In summary, Goji supplementation confers protective effects against DSS&shy;induced colitis, which has the potential to be used as a complementary therapeutic approach for alleviating inflammatory bowel disease symptoms.</p><br /> <p>&nbsp;</p><br /> <p>Dr. David Williams (Oregon State University)</p><br /> <p>We continue to utilize the mouse transplacental cancer chemoprevention model with a focus on the mechanism of transplacental polycyclic aromatic hydrocarbon (PAH)-induced cancer in the offspring as adults following <em>in utero</em> PAH exposure and its chemoprevention by maternal dietary supplementation with indole-3-carbinol (I3C). PAHs are formed from the incomplete combustion of organic material (coal, tobacco, wood, petroleum products, etc.). PAHs are a major health concern and represent 3 of the top 10 chemicals of concern at high priority polluted sites as evaluated by ATSDR (Agency for Toxic Substances Disease Registry, a component of the CDC). It has been estimated that 95% of exposure (for a non-smoker) to carcinogenic PAHs is through diet. We found epigenetic markers such as DNA methylation and profiles of non-coding RNAs were markedly altered in newborns from mothers exposed to a carcinogenic PAH in her diet and these alterations in the epigenome could be partially ameliorated by maternal dietary I3C.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Donato Romagnolo (University of Arizona)</span></p><br /> <p>The farnesoid X receptor (FXR) regulates bile acids (BA) metabolism and possesses tumor suppressor functions. The expression of FXR is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (<em>APC</em>). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention.</p><br /> <p>The objective of our current study was to investigate the influence of <em>APC</em> inactivation on regulation of <em>FXR</em> expression in colonic mucosal cells. We hypothesized that inactivation of <em>APC</em> epigenetically represses <em>NR1H4</em> (<em>FXR</em> gene name) expression through increased CpG methylation. Normal proximal colonic mucosa, and normal-appearing adjacent colonic mucosa and colon tumors were collected respectively from wild-type C57BL/6J and <em>Apc</em> deficient (<em>Apc^Min</em>^/+) male mice. The expression of <em>Fxr</em>, ileal bile acid-binding protein (<em>Ibabp</em>), small heterodimer partner (<em>Shp</em>), and cyclooxygenase-2 (<em>Cox-2</em>) were determined by real-time PCR. In both normal, and adjacent colonic mucosa and colon tumors, we measured CpG methylation of <em>Fxr</em> in bisulfonated genomic DNA. In vitro, we measured the impact of <em>APC</em> inactivation and deoxycholic acid (DCA) treatment on <em>FXR </em>expression in human colon cancer HCT-116 cells transfected with silencing RNA for <em>APC </em>(si<em>APC</em>), and HT-29 cells carrying inactivated APC.</p><br /> <p>In <em>Apc^{Min/ +}</em>mice, constitutive CpG methylation of the <em>Fxr3/4</em> promoter was linked to reduced (60-90%) baseline <em>Fxr</em>, <em>Ibabp</em>, and <em>Shp</em>, and increased <em>Cox-2</em>, expression in apparently normal adjacent mucosa and colon tumors. The knock-down of <em>APC</em> in HCT-116 cells increased <em>c-MYC, </em>and lowered (~50%) <em>FXR </em>expression, which was further reduced (~80%) by DCA. In human HCT-116, but not HT-29 colon cancer cells, DCA induced <em>FXR</em> expression and lowered CpG methylation of <em>FXR</em>. We concluded that in mouse colonic mucosa and human colon cells loss of APC function may favor silencing of FXR expression through CpG hypermethylation leading to reduced expression of downstream targets (SHP, IBABP) involved in BA homeostasis while increasing expression of factors (COX-2, c-MYC) that contribute to inflammation and colon cancer.</p><br /> <p>Future studies will examine the differential effects of various HFD (i.e. n-6 vs n-3) on <em>FXR</em> CpG methylation in normal and <em>APC</em>-deficient colon models. A second question pertains to whether other epigenetic regulatory defects associate with tumor development in APC-deficient colon cells.</p><br /> <p>&nbsp;</p><br /> <p><strong>OBJECTIVE 2. Elucidate mechanisms of action of dietary toxicants and develop biomarkers for human risk assessment and disease prevention.</strong></p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. William Helferich (University of Illinois)</span></p><br /> <p>A soy flour diet (MS) prevented isoflavones from stimulating MCF-7 tumor growth in athymic nude mice, indicating that other bioactive compounds in soy can negate the estrogenic properties of isoflavones. The underlying signal transduction pathways to explain the protective effects of soy flour consumption were studied. Ovariectomized athymic nude mice inoculated with MCF-7 human breast cancer cells were fed either MS or purified isoflavone mix (MI), both with equivalent amounts of genistein. Positive controls received estradiol pellets and negative controls received sham pellets. GeneChip-Human-Genome-U133-Plus-2.0 Array platform was used to evaluate gene expressions, and results were analyzed using bioinformatics approaches. Tumors in MS-fed mice exhibited higher expression of tumor-growth-suppressing genes ATP2A3 and BLNK, and lower expression of oncogene MYC. Tumors in MI-fed mice expressed higher level of oncogene MYB and lower level of MHC-I and MHC-II, allowing tumor cells to escape immunosurveillance. MS induced gene expression alterations were predictive of prolonged survival among estrogen receptor- positive breast cancer patients, whilst MI-induced gene changes were predictive of shortened survival. Our findings suggest dietary soy flour affects gene expression differently than purified isoflavones, which may explain why soy foods prevent isoflavones-induced stimulation of MCF-7 tumor growth in athymic nude mice.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. David Williams (Oregon State University) </span></p><br /> <p>This laboratory has been the first to utilize accelerator mass spectrometry (Lawrence Livermore National Laboratory, LLNL) to follow uptake and elimination in humans of PAHs at an environmentally relevant level of exposure (10% or less of average daily exposure). Using this technology, we can measure femtograms (10^-15) of PAH/ml of blood. Ten femtograms/ml of blood is equivalent to 1 drop of water in 4000 Olympic-sized swimming pools. The current NIEHS-funded project was given an FDA IND (#117175, &ldquo;Pharmacokinetics of [¹⁴C]-Benzo[a]pyrene by Micro-Dosing&rdquo;) as well as Oregon State University and LLNL IRB approvals. Utilizing a new ULPC interface to the AMS instrument, we are able to measure BaP and metabolites in blood and urine rather than just [¹⁴C]. Results to date show significant metabolism (mostly BaP-7,8-dihydrodiol), along with unknown metabolites including what we believe to be conjugates with glutathione, glucuronic acid or sulfate. There is little intra-individual variation in the metabolite profile and parent BaP, but significant differences between individuals, some of which may be related to <em>CYP1B1</em> and/or <em>GSTM1</em> genotypes. Finally, ingestion of smoked salmon, containing a complex mixture of PAHs, along with the [¹⁴C]-BaP markedly reduces blood levels of BaP and its metabolites although we have not run a sufficient number of individuals to assess statistical significance.</p><br /> <p>&nbsp;</p><br /> <p>Dr. Abby Benninghoff (Utah State University)</p><br /> <p>Dr. Benninghoff&rsquo;s&nbsp;group, in collaboration with her colleagues at USU, is investigating the impacts of basal diet and&nbsp;dietary supplements on composition of the gut&nbsp;microbiome in a mouse model of colitis-associated colorectal cancer. &nbsp;Mice were fed&nbsp;either a standard basal diet, AIN93G, or the total Western diet (TWD) for 16 weeks; at week 2 mice were dosed with azoxymethane and provided dextran sodium sulfate to induce colon tumorigenesis. &nbsp;The composition of the fecal microbiome was assessed by 16S sequencing and comparisons between diet groups were made at each stage of disease development (pre-initiation, colitis, recovery, pronounced cancer). &nbsp;Prior to initiation with AOM/DSS, the gut microbiome compositions of AIN93G- and TWD-fed mice were very similar.&nbsp; As colitis progressed, the populations became more distinct, especially so by the recovery stage (day 45), which was also typified by sustained colonic inflammation and mucosal injury in TWD-fed mice.&nbsp; By the study end (day 105), separation between the fecal microbiomes for the different diet groups was evident.&nbsp; Finally, examination of the terminal fecal microbiome revealed distinct gut microbiota profiles for TWD-fed animals initiated with AOM/DSS compared to sham mice, whereas a distinction was not evident for those fed AIN93G. &nbsp;In summary, mice with pronounced colitis-associated colorectal cancer, induced by dietary exposure to TWD, harbored&nbsp;microbiomes distinct from their counterparts fed healthy diets.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Jim Pestka (Michigan State University)</span></p><br /> <p>Deoxynivalenol (DON or "vomitoxin"), a trichothecene mycotoxin produced by Fusarium, is a global food safety concern because it commonly contaminates cereal grains and has the potential to cause growth suppression and gastrointestinal disease in humans. Climate change, modified agricultural practices and recent globalization of trade in agricultural plants have increased Fusarium cereal blight, thereby greatly increasing grain contamination by DON and markedly expanding the contaminant profile to include other structurally-related 8-ketotrichothecenes (3-ADON, 15-ADON, nivalenol, fusarenon X) as well as plant glucosidic metabolites such as DON-3-glucoside. Existing data are insufficient to predict the toxicity risks from exposure to mixtures in these emerging trichothecenes. We are testing the hypothesis that toxic equivalency factors (TEFs) for the 8-ketotrichothecenes derived from DON toxicity models will be applicable to food safety risk assessment and toxicity analysis. Currently we are applying this knowledge by developing a simple in vitro assay that will enable measurement of the trichothecene toxic equivalents in food samples for use as an intervention tool. Toward this end, several candidate enteroendocrine cell lines and endpoints (calcium mobilization, hormone secretion) have been identified.</p><br /> <p>&nbsp;</p><br /> <p><strong>OBJECTIVE 3. Discover and characterize novel bioactive dietary compounds that have beneficial or adverse effects on human health.</strong></p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Michael Denison (UC Davis)</span></p><br /> <p>Estrogenic endocrine disrupting chemicals are found in environmental and biological samples, commercial and consumer products, food, and numerous other sources. We previously developed an estrogen-responsive recombinant human variant breast cancer cell line (vM7Luc4E2) that has been approved by the USEPA and OECD for use as a bioanalytical method to detect estrogen receptor (ER) agonists/antagonists and used this cell line to screen a wide variety of chemicals and commercial/consumer products for estrogenic activity. Although this cell line has been extremely useful for screening purposes and it is being used by many laboratories, these cells have a major limitation for comprehensive screening. vM7Luc4E2 cells contain only one of the two known ER isoforms, ERa but not ERb and the differential ligand selectivity/specificity of these two ERs indicates that the currently accepted screening method only detects a subset of the total number of estrogenic chemicals. To improve the estrogen screening bioassay, vM7Luc4E2 cells were stably transfected with an ERb expression plasmid and positive clones identified using ERb-selective ligands (genistein and Br-ERb-041). A highly responsive clone (vM7Luc4E2bc9) was identified that exhibited greater sensitivity and responsiveness to ERb-selective ligands than vM7Luc4E2 cells and qRT-PCR confirmed the presence of ERb expression in these cells. Screening of a small library of 173 pesticides and industrial chemicals not only identified chemicals that could activate both ERs but they also revealed chemicals that preferentially stimulated ERb-dependent reporter gene expression. Together, these results not only demonstrate the utility of this new dual ER recombinant cell line for detecting a broader range of estrogenic chemicals than the currently approved vM7Luc4E2 cell line, but screening with both vM7Luc4E2 and vM7Luc4E2bc9 cell lines allows identification of ERa and ERb-selective chemicals.</p><br /> <p>During the past year, we started screening commercially prepared food products for the presence of estrogenic chemicals using our recombinant cell lines. Initial screening studies revealed the presence of very high concentrations of estrogenic activity in ethanol extracts of Nabisco Nilla Wafer cookies (producing ~50% of maximal estrogenic activity with only the equivalent of 10 mg of cookie extract using the vM7Luc4E2 cell line). Given the unexpected nature of this finding, we questioned whether other cookies also contained high levels of estrogenic activity and subsequently obtained a number of different products (focusing only on cookies that lacked frosting, glazes, sprinkles or other potential confounding additives). The specific products we selected for this analysis included cookies from Nabisco (Nilla Wafers, Lorna Doones, Animal Crackers, Oreos, Saltines), Pepperidge Farms (Bordeaux, Chessman) and Walkers (Shortbread). We analyzed multiple extracts of three different lots/batches of each of these products and our studies to date revealed tremendously high estrogenic activity in vM7Luc4E2 cells incubated with extracts from the Nabisco products, with only moderate or low activity in extracts from Walkers and Pepperidge Farms products. Interestingly, substantially higher activity was detected using the new vM7Luc4E2bc9 cell line (producing up to 80% of maximal estrogenic activity with an extract volume equivalent to only 5 mg of original cookie). These results not only indicated the presence of chemicals that can activate both forms of ER, but they also revealed the presence of chemicals that selectively activated ERb signaling. Interestingly, the extracts of Lorna Doone and Animal crackers contained the highest estrogenic activity of all products examined to date (producing between 50-80% of maximal estrogenic activity with an extract that is equivalent to 5 mg of original cookie).&nbsp;&nbsp; However, considering that the weight of one Lorna Doones is about 7 grams and a serving is 4 cookies (~28 grams), there is potential for exposure to high levels of estrogenic chemicals from consumption of one serving of cookies (if that is all an individual consumes). The presence of estrogenic chemicals in common commercial cookies has not been assessed as far as we are aware and this has opened a potentially interesting and significant area of investigation and will we continue to examine this in detail in the upcoming year. The presence of this activity is particularly of concern when we consider the potential exposure of children, who are major consumers of these products. Interestingly, the extracts showed little or no activity in the Ah receptor cell bioassays, indicating specificity of extract chemicals for the ER signaling pathway. While the extremely high levels of estrogenic activity that one could be exposed to from consumption of these cookies might turn out to be a significant concern, but this would only occur if the active chemicals can be readily absorbed and survive first-pass metabolism. These critical aspects remain to be examined in future studies.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Marie-Louise Ricketts (University of Nevada-Reno)</span></p><br /> <p>Dietary procyanidins are beneficial in maintaining health. Grape seed procyanidin extract (GSPE) in particular has been shown to regulate cholesterol and triglyceride (TG) homeostasis <em>in vivo</em>. Our lab has identified several underlying molecular mechanisms by which GSPE decreases serum TG levels, including farnesoid x receptor (FXR)-dependent decreased hepatic triglyceride synthesis, inhibition of enterohepatic bile acid (BA) recirculation and increased hepatic TG catabolism. Furthermore, we identified GSPE as a histone deacetylase (HDAC) inhibitor, leading to enhanced PPAR<em>&alpha; </em>target-gene transcription and increased fatty acid &beta;-oxidation. Further studies were designed to identify which component (or components) within GSPE are responsible for these effects. In an effort to facilitate further understanding regarding its molecular actions, GSPE was fractionated by column chromatography to separate compounds based on molecular size (n=3). The degree of polymerization for each fraction was determined by HPLC. Using a cell-based transient transfection assay, each fraction was tested in combination with the bile acid, chenodeoxycholic acid (CDCA), to assess its ability to increase FXR transactivation (n=3, analyzed in triplicate). Fractions that demonstrated enhanced transactivation were then analyzed by mass spectrometry. Results show that fractions enriched in dimers and dimer gallates enhance FXR transactivation. Additional <em>in vitro </em>studies are on going to determine whether these fractions regulate gene expression via FXR using Caco2 cells. Ultimately, this study will facilitate enhanced understanding regarding the observed GSPE-mediated regulation of metabolic homeostasis <em>in vivo</em>.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Mendel Friedman (USDA-ARS Albany)</span></p><br /> <p>Processing plant foods at elevated temperatures forms Acrylamide, a potential carcinogen. A wide range in the acrylamide concentrations has been found in commercial canned black ripe olives. This group&rsquo;s work has resulted in optimized, safe thermal processing conditions that are an efficient alternative to current approaches, and leads to reduced acrylamide formation during thermal processing of olives and improved quality of black ripe olives.</p><br /> <p>Optimized techniques for analysis of food composition are needed to improve the ability to relate their function to their chemical composition. This group has worked on approaches to determine protein amino acids and metabolites, non-protein amino acids, dietary protein, glucose, fructose, sucrose, phenolic, and flavonoid content and antioxidative properties of potato tubers, peels, and pulps. The methods they describe might facilitate the analysis of potato cultivars, peels, and pulps and relate their composition and antioxidative activities to their nutritional and health-promoting properties.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Donato Romagnolo (University of Arizona)</span></p><br /> <p>Only 5-10% of breast cancer cases is linked to germline mutations in the <em>BRCA-1</em> gene and occurs early in life. Conversely, sporadic breast tumors, which represent 90-95% of breast malignancies, have lower BRCA-1 expression, but not a mutated <em>BRCA-1 </em>gene, and tend to occur later in life in combination with other genetic alterations and/or environmental exposures. The latter may include environmental and dietary factors that activate the aromatic hydrocarbon receptor (AhR). Therefore, understanding if changes in expression and/or activation of the AhR are associated with somatic inactivation of the <em>BRCA-1</em> gene may provide clues for breast cancer therapy.</p><br /> <p>We evaluated <em>Brca-1</em> CpG promoter methylation and expression in mammary tumors induced in Sprague-Dawley rats with the AhR agonist and mammary carcinogen 7,12-dimethyl-benzo(a)anthracene (DMBA). Also, we tested in human estrogen receptor (ER)-negative sporadic UACC-3199 and ERa-positive MCF-7 breast cancer cells carrying respectively, hyper- and hypomethylated <em>BRCA-1</em> gene, if the treatment with the AhR antagonist a-naphthoflavone (aNF) modulated BRCA-1 and ERa expression. Finally, we examined the association between expression of <em>AhR</em> and <em>BRCA-1</em> promoter CpG methylation in human triple-negative (TNBC), luminal-A (LUM-A), LUM-B, and epidermal growth factor receptor-2 (HER-2)-positive breast tumor samples.</p><br /> <p>Mammary tumors induced with DMBA had reduced BRCA-1 and ERa expression; higher <em>Brca-1</em> promoter CpG methylation; increased expression of <em>Ahr</em> and its downstream target <em>Cyp1b1</em>; and higher proliferation markers <em>Ccnd1</em> (cyclin D1) and <em>Cdk4</em>. In human UACC-3199 cells, low BRCA-1 was paralleled by constitutive high AhR expression; the treatment with aNF rescued BRCA-1 and ERa, while enhancing preferential expression of <em>CYP1A1</em> compared to <em>CYP1B1</em>. Conversely, in MCF-7 cells, aNF antagonized estradiol-dependent activation of BRCA-1 without effects on expression of ERa. TNBC exhibited increased basal <em>AhR</em> and <em>BRCA-1</em> promoter CpG methylation compared to LUM-A, LUM-B, and HER-2-positive breast tumors.</p><br /> <p>Constitutive AhR expression coupled to <em>BRCA-1</em> promoter CpG hypermethylation may be predictive markers of ERa-negative breast tumor development. Ongoing studies in our laboratory are using in vitro and vivo models to explore the effects of AhR knockout on epigenetic regulation of <em>BRCA-1</em> and <em>ESR1</em> (ERa, and the preventative effects of AhR antagonists. Progress in these areas may help clarifying a causative role for the AhR in breast tumorigenesis and assist with the development of risk models for <em>BRCA-1</em> mutation carriers and sporadic TNBC, for which therapy options remains an intensive area of investigation.</p><br /> <p>&nbsp;</p><br /> <p><span style="text-decoration: underline;">Dr. Tiffany Weir (Colorado State University)</span></p><br /> <p>Noni juice is used traditionally in Polynesian cultures to relieve a variety of ailments and can be consumed fermented or non-fermented. However, fermentation alters the chemical profile and may change the bioactivity profile of the noni juice. In collaboration with Dr. Pratibha Nerurkar, who examines the effect of noni juice on high fat diet-induced diabetes in mice, we are exploring metabolomic profiles of fermented and non-fermented noni juices. We have found that fermentation is the primary source of variability in global metabolomic profiles of noni. However, these changes do not appear to be specifically associated with protection against metabolic impairments in high fat diet-fed mice.</p><br /> <p><strong>&nbsp;</strong></p><br /> <p><strong>OBJECTIVE 4. Increase beneficial or decrease adverse effects of bioactive constituents and microbes in food.</strong></p><br /> <p><strong>&nbsp;</strong></p><br /> <p><span style="text-decoration: underline;">Dr. Mendel Friedman (USDA-ARS Albany)</span></p><br /> <p>Microbial contaminants in foods are a potential safety issue for humans and animals. Work by Friedman and colleagues have found that the glycoalkaloid tomatine found in tomatoes exhibited potent antimicrobial activity against pathogenic protozoa (<em>Trichomonas vaginalis</em>) that infect humans, cattle, and cats. Their results suggest its potential value for developing alternative therapy toward trichomoniasis in humans, bovines, and felines. In other studies, they found that a commercial pomegranate preparation reduced the heat resistance of the virulent pathogen <em>Escherichia coli</em> O104:H4 in ground chicken, suggesting that meat processors can use the described kinetic model to design lethality treatments in order to achieve specific reductions of the pathogen in ground poultry products at lower processing temperatures.</p><br /> <p>Eliminating microbial contaminants from plant-based foods is particularly problematic. This group has explored the impact of several plant-based antimicrobial washes on the sensory properties of organic leafy greens (celery, lettuce, and spinach). The showed that greens treated with 0.1% cinnamaldehyde had the highest preference liking by the 60 panelists, suggesting its value for large-scale (industrial) use to improve microbial food safety.</p><br /> <p><span style="text-decoration: underline;">Dr. David Williams (Oregon State University) </span></p><br /> <p>A major effort this past year has been focused on reducing human health risks from food-borne pathogens and environmental contaminants. I3C and SFN are especially potent in reducing the risk to the fetus from exposure <em>in utero</em> to chemical carcinogens ingested in food as well as adult cancers.</p><br /> <p><span style="text-decoration: underline;">Dr. Meijun Zhu (Washington State University)</span></p><br /> <p>Treatment of <em>E. coli</em> O157:H7 infection is difficult since many antibiotics are shown to induce SOS response and enhance Stx production. Thus, an alternative antimicrobial intervention of <em>E. coli</em> O157:H7 in human infection is needed. Cinnamon is an antimicrobial spice that has been widely used for thousands of years. We found that Cinnamon oil not only effectively inhibited growth of <em>E. coli</em> O157:H7 at high concentration, but also dramatically reduced both Stx2 phage and total phage induction in <em>E. coli</em> O157:H7 at a sub-inhibitory concentration. The inhibitory effect might be due to the suppression of bacterial SOS response key regulator RecA and vital RNA polyadenylation enzymes (PNPase and PAP I). Additionally, <em>C. cassia</em> oil has bactericidal effects against bovine mastitis pathogenic isolates possibly through disruption of membrane structure. These data suggest its potential application as a therapeutic to control pathogenic bacterial infections.</p>

Publications

<p>Amin, ARMR, Karpowicz, PA, Carey, TE, Arbiser, J, Nahta, R, Chen, ZG, Dong, J-T, Kucuk, O, Khan, GN, Huang, GS, Mi, S, Lee, H-Y, Reichrath, J, Honoki, K, Georgakilas, AG, Amedei, A, Amin, A, <strong>Helferich, B,</strong> Boosani, CS, Ciriolo, MR, Chen, S, Mohammed, SI, Azmi, AS, Keith, WN, Bhakta, D, Halicka, D, Niccolai, E, Fujii, H, Aquilano, K, Ashraf, SS, Nowsheen, S, Yang, X, Bilsland, A, Shin, DM, 2015. Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds. Semin Cancer Biol. Mar 5. pii: S1044-579X(15)00013-9. doi: 10.1016/j.semcancer.2015.02.005. [Epub ahead of print] Review. PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25749195">25749195</a></p><br /> <p>Andruska, N, Zheng, X, Yang, X, Mao, C, Cherian, MM, Mahapatra, L, <strong>Helferich, WG</strong> and Shapiro, DJ., 2015. Estrogen receptor a inhibitor activates the unfolded protein response, blocks protein synthesis and induces tumor regression. Proc Natl Acad Sci USA. Mar 30. pii: 201403685. [Epub ahead of print] PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25825714">25825714</a></p><br /> <p>Atwell, L.L., Beaver, L.M., Shannon, J., <strong>Williams, D.E</strong>., Dashwood, R.H. and Ho, E., 2015. Epigenetic regulation by sulforaphane: Opportunities for breast and prostate cancer chemoprevention. Current Pharmacol. Reports. 1:102-111.</p><br /> <p>Atwell, L.L., Hsu, A., Beaver, L.M., Stevens, J.F., Choi, J., Jiang, Y., Bella, D., <strong>Williams, D.E</strong>., Shannon, J., Dashwood, R.H. and Ho, E., 2016. Untargeted metabolic screen reveals changes in human plasma metabolite profiles following consumption of fresh broccoli sprouts. <strong><em>Food Func.</em></strong>, in press.</p><br /> <p>Aumsuwan, P, Khan, SI, Khan, IA, Ali, Z, Avula, B, Walker, LA, Shariat-Madar, Z, <strong>Helferich, WG</strong>, Katzenellenbogen, BS, Dasmahapatra, AK., 2015. The anticancer potential of steroidal saponin, dioscin, isolated from wild yam (Dioscorea villosa) root extract in invasive human breast cancer cell line MDA-MB-231 in vitro. Arch Biochem Biophys. Dec 9. pii: S0003-9861(15)30112-0. doi: 10.1016/j.abb.2015.12.001. [Epub ahead of print] PMID:<a href="http://www.ncbi.nlm.nih.gov/pubmed/26682631">26682631</a></p><br /> <p>Bak, S.-M., Iida, M., Soshilov, A.A., <strong>Denison, M.S.</strong>, Iwata, H. and Kim, E.-Y., 2016. Auto-induction mechanism of aryl hydrocarbon receptor 2 (AHR2) gene by TCDD-activated AHR1 and AHR2 in the red seabream (<em>Pagrus major</em>), Arch. Toxicol., In Press. PMID: 27188387</p><br /> <p>Banerjee, N., Kim, H., Talcott, S.T., <strong>Turner, N.D.</strong>, Byrne, D.H., and Mertens-Talcott, S.U., 2016. Plum polyphenols inhibit colorectal aberrant crypt foci formation in rats: Potential role of the miR-143/protein kinase B/mammalian target of rapamycin axis. Nutrition Research 36, 1105-1113.</p><br /> <p>Bates, M.A., Brandenberger, C., Langohr, II, Kumagai, K., Lock, A.L., Harkema, J.R., Holian, A., <strong>Pestka, J.J.</strong>, 2016. Silica-triggered autoimmunity in lupus-prone mice blocked by docosahexaenoic acid consumption. PLoS One 11, e0160622.</p><br /> <p>Bibi, S., Kang, Y., Yang, G., and <strong>Zhu</strong>, <strong>M.J.</strong>, 2016. Grape seed extract improves small intestinal morphology through suppressing inflammation and regulating alkaline phosphatase in IL10-deficient mice. Journal of Functional Food, 20: 245-252.</p><br /> <p>Block, KI, Gyllenhaal, C, Lowe, L, Amedei, A, Amin, ARMR, et al., 2015. A broad-spectrum integrative design for cancer prevention and therapy. Semin Cancer Biol. 35 Suppl:S276-304. doi: 10.1016/j.semcancer.2015.09.007. PMID:<a href="http://www.ncbi.nlm.nih.gov/pubmed/26590477">26590477</a></p><br /> <p>Boonmuen, N, Gong, P, Ali, Z, Chittiboyina, AG, Khan, I, Doerge, DR, <strong>Helferich, WG</strong>, Carlson, KE, Martin, T, Piyachaturawat, P, Katzenellenbogen, JA, Katzenellenbogen, BS., 2015. Licorice root components in dietary supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic activities. Steroids. 105, 42-49. doi: 10.1016/j.steroids.2015.11.006. [Epub ahead of print] PMID:<a href="http://www.ncbi.nlm.nih.gov/pubmed/26631549">26631549</a></p><br /> <h3>Borresen, E., Brown, D.G., Harbison, G., Taylor, L., Fairbanks, A., O&rsquo;Malia, J., Bazan, M., Rao, S., Baily, S., Wdowik, M., Weir, T.L., Brown, R.J., Ryan, E.P., 2016. A randomized-controlled trial to increase navy bean or rice bran consumption in colorectal cancer survivors. Nutrition &amp; Cancer<em>. </em>Dx.doi.org/10.1080/01635581.2016.1224370.</h3><br /> <p>Brennan, J.C., Bassal, A., He, G. and <strong>Denison, M.S.</strong>, 2016. Development of a recombinant human ovarian (BG1) cell line containing estrogen receptor a and b for improved detection of estrogenic/antiestrogenic chemicals. Environ. Toxicol. Chem. 35, 91-100. PMC4772679</p><br /> <p>Brown, D.G., Rao, S., <strong>Weir, T.L.</strong>, O&rsquo;Malia, J., Bazan, M., Brown, R.J., Ryan, E.P., 2016. Metabolomics investigation of tumors, adjacent colonic mucosa and stool from colorectal cancer patients. Cancer &amp; Metabolism 4:11.</p><br /> <p>Cai, K, Yen, J, Yin, Q, Liu, Y, Song, Z, Lezmi, S, Zhang, Y, Yang, X, <strong>Helferich, WG</strong>, and Cheng, J., 2015. Redox-responsive self-assembled chain-shattering polymeric therapeutics. Biomater Sci. 3, 1061-1065. PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26146551">26146551</a></p><br /> <p>Casey, SC, Amedei, A, Aquilano, K, Benencia, F, Bhakta, D, Boosani, CS, Chen, S, Ciriolo, MR, Crawford, S, Fujii, H, Georgakilas, AG, Guha, G, Halicka, D, <strong>Helferich, WG</strong>, Heneberg, P, Honoki, K, Kerkar, SP, Mohammed, SI, Niccolai, E, Nowsheen, S, Vasantha Rupasinghe, HP, Samadi, A, Singh, N, Talib, WH, Venkateswaran, V, Whelan, RL, Yang, X, Felsher, DW., 2015. Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin Cancer Biol. Apr 9. pii: S1044-579X(15)00015-2. doi: 10.1016/j.semcancer.2015.02.007. [Epub ahead of print] Review. PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25865775">25865775</a>.</p><br /> <p>Choi, S.-H., Kozukue, N., and <strong>Friedman, M.</strong>, 2016. Composition and antioxidative and cancer cell inhibiting activities of Jujube fruits and seeds (<em>Ziziphus jujuba</em>) cultivated in Korea. In <em>Chinese Dates: A Traditional Functional Food</em>, Liu, D.; Ye, X.; Jiang, Y., Eds. CRC Press: Boca Raton, FL, pp 99-114.</p><br /> <p>Choi, S.-H., Kozukue, N., Kim, H.-J., and <strong>Friedman, M.</strong>, 2016. Analysis of protein amino acids, non-protein amino acids and metabolites, dietary protein, glucose, fructose, sucrose, phenolic, and flavonoid content and antioxidative properties of potato tubers, peels, and cortexes (pulps). J. Food Compos. Anal. 50, 77-87.</p><br /> <p>Clark, E.S., Flannery, B.M., Gardner, E.M., <strong>Pestka, J.J.</strong>, 2015a. High sensitivity of aged mice to deoxynivalenol (Vomitoxin)-induced anorexia corresponds to elevated proinflammatory cytokine and satiety hormone responses. Toxins (Basel) 7, 4199-4215.</p><br /> <p>Clark, E.S., Flannery, B.M., <strong>Pestka, J.J.</strong>, 2015b. Murine anorectic response to deoxynivalenol (vomitoxin) is sex-dependent. toxins (Basel) 7, 2845-2859.</p><br /> <p>Cole, B., Brander, S., Jeffries, K., Hasenbein, S., He, G., <strong>Denison, M.S.</strong>, Fangue, N. and Connon, R., 2016. Changes in menidia beryllina gene expression and <em>in vitro</em> hormone receptor activation following exposure to estuarine waters near treated wastewater outfalls, Arch. Environ. Contam. Toxicol. 71, 210-223. PMID: 27155869</p><br /> <p>Corrada, D., Soshilov, A.A., <strong>Denison, M.S.</strong> and Bonati, L., 2016. Deciphering dimerization modes of PAS domains: Computational and experimental analyses of the AhR:ARNT complex reveal new insights into the mechanisms of AhR transformation, PLoS Comp. Biol. 12(6), e1004981. PMC4905635</p><br /> <p>Cox-York, K, Sheflin, AM, Foster, MT, Gentile, CL, Kahl, A, Koch, L, Britton, S, <strong>Weir, TL</strong>, 2015. 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Impact Statements

1. • Demonstrated that pregnant females exposed to PAHs transfer those carcinogens to the fetus and the offspring develop cancer. Indole-3-carbinol (I3C), from cruciferous vegetables, when added to the mother’s diet protects the fetus. Both the production of the “transplacental” cancer and its inhibition by I3C involved both genotoxicity and alterations in epigenetic parameters such as DNA methylation and microRNA (miRNA) profiles.

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