Brief Summary of Minutes of Annual Meeting

OBJECTIVE 1. Determine the mechanisms by which dietary bioactive compounds protect against human diseases. 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. 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. 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. 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. 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. 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. 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. OBJECTIVE 2. Elucidate mechanisms of action of dietary toxicants and develop biomarkers for human risk assessment and disease prevention. 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. 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. 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. 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. OBJECTIVE 3. Discover and characterize novel bioactive dietary compounds that have beneficial or adverse effects on human health. 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. 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. 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. OBJECTIVE 4. Increase beneficial or decrease adverse effects of bioactive constituents and microbes in food. 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. 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. 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. 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. 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

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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. Petrovi, D.; Sivapragasam, N.; Thavarajah, D.; Gelling, V.; Thavarajah, P. Resistant starch nanoparticles for potential colonic drug and nutrient delivery. Biomacromolecules (in preparation) 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 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. 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