W1122: Beneficial and Adverse Effects of Natural, Bioactive Dietary Chemicals on Human Health and Food Safety

(Multistate Research Project)

Status: Inactive/Terminating

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SAES-422 Reports

Annual/Termination Reports:

[09/19/2003] [08/23/2004] [10/25/2004] [11/01/2005] [01/12/2007]

Date of Annual Report: 09/19/2003

Report Information

Annual Meeting Dates: 10/10/2002 - 10/11/2002
Period the Report Covers: 10/01/2001 - 09/01/2002

Participants

Administrative Advisor Richard Heimsch (Idaho), committee members George Bailey (Oregon), Len Bjeldanes (UC Berkeley), Roger Coulombe (Utah), Mendel Friedman (USDA-WRRC Albany, CA), Bill Helferich (Illinois), Jim Pestka (Michigan State), Ron Riley (USDA-ARS Athens, GA), Jorge Vivanco (Colorado State), and Carl Winter (UC Davis).

Brief Summary of Minutes

W-1122: Beneficial and Adverse Effects of Natural, Bioactive Dietary Chemicals on Human Health and Food Safety

Annual meeting of the technical committee, October 10-11, 2002 Calistoga, CA

The annual meeting was called to order at 0830 Thursday morning, October 10th. Present were Administrative Advisor Richard Heimsch (Idaho), committee members George Bailey (Oregon), Len Bjeldanes (UC Berkeley), Roger Coulombe (Utah), Mendel Friedman (USDA-WRRC Albany, CA), Bill Helferich (Illinois), Jim Pestka (Michigan State), Ron Riley (USDA-ARS Athens, GA), Jorge Vivanco (Colorado State), and Carl Winter (UC Davis).

Advisor Heimsch reported that our renewal proposal was finally approved after a long process. Now named W-1122, our project is approved for another five years, until September 30, 2007. Annual reports, summaries, and other entries relating to the project are now to be made online through NIMS- the National Information Management System, working through local Agricultural Experiment Stations. NIMS can be accessed at http://www.colostate.edu/Orgs/WAAESD/ under "Multi-State Research." Committee members were reminded that the "impacts" section of their annual reports are an increasingly important validation of our project, as they are scrutinized by various stakeholders.

Heimsch introduced the two new committee members, Assistant Professor Jorge Vivanco of the Department of Horticulture and Landscape Architecture, Colorado State University, and Ron Riley, of the USDA-ARS Mycotoxin Research Laboratory in Athens, GA. The committee welcomed these new members. In that context, committee members discussed further strengthening W-1122 by continuing to recruit new members. Cathy Davis (U. Delaware) and Berna Magnusson (U Maryland) were identified as possible collaborators.

After these initial items, the annual reports were given.

The regular business portion of the meeting commenced Friday morning at 0930. Ron Riley was elected secretary for the 2003 meeting. He will be responsible for taking minutes of the meeting. Other officers for the upcoming year will be Roger Coulombe, Chair, and Jorge Vivanco, Vice Chair. Colorado and Utah were suggested as possible meeting locations. October 9-10 was agreed upon as the meeting dates.

Accomplishments

October 1, 2001 to September 30, 2002 PROJECT: W-1122 Beneficial and Adverse Effects of Natural, Bioactive Dietary Chemicals on Human Health and Food Safety COOPERATING AGENCIES AND PRINCIPAL LEADERS: A. Experiment Stations: California: L. Bjeldanes (UCB) and C. Winter (UCD); Colorado (CSU): J. Vivanco; Idaho (ID): J. Exon; Illinois (IL): W. Helferich; Michigan (MSU): J. Pestka; Oregon (OSU): G. Bailey; Utah (USU): R. Coulombe. B. Other Cooperating Agencies: Western Regional Research Center (WRRC), USDA-ARS, Albany: M. Friedman; Richard B. Russell Research Center, USDA-ARS, Athens, GA: R. Riley. C. Administrative Advisor: R. Heimsch, University of Idaho PROGRESS OF WORK: OBJECTIVE 1: Investigate the cellular and molecular modes of action by which natural bioactive chemicals in food protect against human diseases such as cancer, inflammation and microbial infection. In an investigation of the mechanism of ligand-independent activation of the estrogen receptor by 3,3‘-diindolymethane (DIM) in Ishikawa and HEC-1B human endometrial cancer-derived cells, it was found that DIM stimulated the activity of an ER-responsive reporter by up to over 40 fold. The DIM stimulatory effect was abolished when cells were co-treated with the estrogen receptor antagonist ICI-182,780, confirming that activation of the estrogen receptor was necessary for the observed effect. DIM activation was also reduced by 75% and 50%, respectively, from co-treatment of the PKA inhibitor H89 or the MAPK inhibitor PD98059. DIM is a mechanistically novel activator of the estrogen receptor that requires PKA-dependent phosphorylation of CREB and AF-2 transcriptional activity. (CA-B) DIM was also found to exhibit potent antiproliferative and antiandrogenic properties in androgen dependent human prostate cancer cells. DIM inhibited transcription of the endogenous PSA gene and transfected chimeric PSA reporter constructs and also resulted in decreased levels of secreted and intracellular PSA protein expression induced by dihydrotestosterone. Results indicate that DIM is a potent antagonist of androgen function in prostate tumor cells and establish DIM as a unique bifunctionally active hormone disruptor. (CA-B) Younger rats had significantly greater numbers of aberrant crypt foci than did older rats when the rats were fed vitamin E in the form of d-alpha tocopheryl succinate. (ID) A study was conducted to determine the ability of dietary genistein to negate or overwhelm the effectiveness of tamoxifen (TAM). In the presence of TAM estradiol implants, no growth of estrogen dependent tumor growth was observed. When genestein was present in the diet a significant increase in tumor growth was observed. (IL) Soy components were fractionated into several fractions from soy flour and isocaloric and isonitrogenous diets containing the different fractions were provided to mice. There was a significant difference in the tumor growth rate when mice consumed whole soy flour, suggesting that there are compounds in soy flour that reduce bioavailability of genestein or that there are other bioactive products in soy that can alter the effect of genestein. (IL) The two main omega-3 polyunsaturated fatty acids in fish oil, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were studied to determine their abilities to retard progression of Primary IgA nephropathy (IgAN) in mice induced by the tricothecene mycotoxin deoxynivalenol (DON). DON significantly increased serum IgA, serum IgA immune complexes and kidney mesangial IgA deposition. DHA, EPA, and DHA/EPA treatment significantly attenuated all three immunopathological parameters as compared to control + DON groups and also significantly reduced IgA secretion by spleen cells. (MSU) It was shown that DON affects expression of multiple genes that may contribute to its immunotoxic effects and this expression profile can be affected by diet containing omega-3 fatty acids. (MSU) Experiments to assess the dose-dose interactions between dietary chlorophyllin (CHL) and dibenzo(a,1)pyrene (DBP) in the trout multi-organ tumorigenesis model. Overall, CHL-mediated reduction in target organ DNA adduction is a predictive biomarker for eventual reduction of tumor risk in both target organs (stomach and liver). (OSU) The effects of green and white teas on tumor development in two mouse models of colorectal cancer are being study. Both teas were shown to effectively suppress tumor development and molecular studies provide evidence that this is, at least in part, suppressing beta-catenin expression in normal intestinal mucosa. (OSU) In collaboration with OSU researchers, a study introducing an efficient AFB1 metabolizing enzyme into plants is underway to potentially increase in situ detoxification of this mycotoxin in the field. The CYP isoform appears to be a "pure epoxidator" in that it forms no other non-epoxidated metabolites. Various CYP-containing gene cassettes are being expressed into E. coli and into Agrobacterium for later tranfection into tobacco and maize. (USU) OBJECTIVE 2: Determine cellular effects and molecular mechanisms of natural and induced toxicants in food for human risk assessment and disease prevention. A murine macrophage model, using RAW 264.7 cells, was used to study the effects of DON-mediated apoptosis and DON upregulation of TNF-alpha and MIP-2 expression. Results also suggested that DON induces a signalling cascade in the macrophage that results in elevated TNF-alpha and MIP-2 gene expression. (MSU) The acute effects of DON on human acute cytokine production in peripheral mononuclear blood leukocytes were studied using a blood culture system. IL-6 and IL-8 were significantly induced by DON as was TNF-alpha. (MSU) The age-related susceptibility of poultry to AFB1 is being studied to potentially explain why younger turkeys are more susceptible to AFB1. Microsomal AFB1 activation was most efficient in the youngest birds while the activity of hepatic cytosolic glutathione S-transferases were deficient in the youngest age group but higher in the older groups. The extreme sensitivity of young turkeys to the toxic effects of AFB1 may result from efficient activation. (USU) OBJECTIVE 3: Detect and identify new natural or induced bioactive compounds in foods that have beneficial or adverse effects on human health. Use of Hypericum perforatum L., commonly known as St. John‘s wort, has increased recently due to the pharmaceutical potential of hypericin found in its leaves. A novel cell culture system for in vitro growth and production of this species was developed. Light and dark conditions, with cell aggregate size, played an important role in growth and hypericin production in cell suspension cultures. (CSU) A major gene termed Hyp-1 encoding for hypericin biosynthesis was cloned and characterized from Hypericum perforatum L. cell cultures. (CSU) The allelopathic capability of the noxious weed Centaurea maculosa (spotted knapweed) was studied. It was found that (-)-catechin is a root-secreted phytotoxin that contributes to C. maculosa‘s invasive behavior in the rhizosphere. (+)-Catechin had antibacterial activity against root infesting pathogens while (-)-catechin did not. Results suggest that each enantiomer of racemic catechin contributes separate properties for plant aggression and defense. (CSU) Potentially bioactive compounds were identified in studies of wild (7 species) and cultivated (2 species) of western Vaccinium including blueberries, huckleberries, and cranberries. The wild Vaccinium species were highest in anthocyanin content. Of the aglycons studied, delphinidin and cyaniding were consistently found in the greatest amount while quercitin was typically found to be the most abundant of the flavonols. (ID) OBJECTIVE 4: Ascertain how agricultural production and food processing may influence production/stability of natural bioactive chemicals. Production of fumonisin mycotoxins produced by the fungus Fusarium moniliforme appears to be strongly influenced by growth conditions. The fungicide metalaxyl appears to be a promising candidate for reducing fumonisin levels as cultures of F. moniliforme grown in media containing the fungicide showed normal fungal growth but significantly reduced levels of fumonisins. Maximum toxin production is observed at pH levels below 3. CA-D) A comprehensive review of the chemical and biological basis of the formation in food and the toxicological effects of acrylamide was developed. (WRRC)

Publications

PUBLICATIONS: CALIFORNIA Leong, H., Firestone, G.L. and Bjeldanes, L.F. Cytostatic effects of 3,3‘-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-alpha expression. Carcinogenesis 22; 1809-1817, 2001. Staub, R.E., Feng, C., Onisko, B.; Bailey, G., Firestone, G.L. and Bjeldanes, L.F. Fate of Indole-3-carbinol in MCF-7 breast cancer cells, Chem. Res. Toxicol. 15:101-109, 2002. Hong, C., Firestone, G.L., and Bjeldanes, L.F. 3,3‘-Diindolymethane (DIM) induces a G1 cell cycle arrest and Bcl-2-mediated apoptosis in human breast cancer cells. J. Biolchem. Pharm. Biochem Pharmacol. 63: 1085-1097, 2002. Hong, C., Kim, Hyeon-A, Firestone, G.L., and Bjeldanes, L.F. 3,3‘-Diindolylmethane (DIM) induces a G1 cell cycle arrest in human breast cancer cells that is accompanied by Sp1-mediated activation of p21 WAFI/CIP1 expression. Carcinogenesis 23: 1297-1305, 2002. Leong, H., Firestone, G.L., and Bjeldanes, L.F. Potent ligand-independent estrogen receptor activation by 3,3‘-diindolymethane is mediated by cross-talk between the PKA and MAPK signaling pathways. (submitted for publication) 2002. Winter, C.K. Electronic information resources for food toxicology. Toxicology 173: 89-96, 2002. (includes discussion of natural toxins) Garcia, E.L., Winter, C.K. Diet and Cancer. In: Cliver, D.O. and H.P. Reimann, eds., Foodborne Diseases, 2nd Edition, Academic Press, New York (in press, November 2002). COLORADO Bais, H.P., Walker, T.S., Schweizer, H., Vivanco, J.M. Root specific elicitation and antimicrobial activity of rosmarinic acid in hairy root cultures of sweet basil (Ocimum basilicum L.). Plant Physiology & Biochemistry (in press) November, 2002. Walker, T.S., Bais, H.P., Schweizer, H.P., Fall, R., Vivanco, J.M. Pseudomonas aeruginosa biofilm: a protective mechanism against plant root-derived antibiotics. Proceedings of the National Academy of Sciences. (Submitted) Park, S-W., Lawrence, C.B., Linden, J.C., Vivanco, J.M. Characterization of a novel ethylene-inducible ribosome-inactivating protein exuded from root cultures of Phytolacca americana. Plant Physiology 130: 164-178, 2002. Park, S-W., Stevens, N., Vivanco, J.M. Enzymatic specificity of three ribosome-inactivating proteins against fungal ribosomes, and correlation with antifungal activity. Planta (in press), 2002. Bais, H.P., Loyola-Vargas, V.M., Flores, H.E., Vivanco, J.M. Root-specific metabolism: the biology and biochemistry of underground organs. In Vitro Cell Dev. - PLANT 37: 730-741, 2001. Vivanco, J.M., Guimaraes, R., Flores, H.E. Underground plant metabolism: the biosynthetic potential of plant roots. In: Plant Roots the Hidden Half. Y. Waisel, A. Eshel, U. Kafkafi, eds., Marcel Dekker Press, new York, pp 1045-1070, 2002. Bais, H.P., Walker, T.S., McGrew, J.J., Vivanco, J.M. Cell size aggregation and dark conditions influence growth and production of hypericin in cell suspension cultures of Hypericum perforatum L. (St. Johns Wort). In Vitro Cell. Dev.-PLANT 38: 58-65, 2002. Walker, T.S., Bais, H.P., Vivanco, J.M. Jasmonic acid-induced hypericin production in cell suspension cultures of Hypericum perforatum L. (St. Johns Wort). Phytochemistry 60 (3): 289-293, 2002. Bais, H.P., Vepachedu, R., Lawrence, C.B., Stermitz, F.R., Vivanco, J.M. Isolation of a gene responsible for formation of the anti-depressive compound hypericin from St. John‘s Wort (Hypericum perforatum L.) reveals a direct and complex mode of chemical synthesis. Submitted to Nature Biotechnology. Bais, H.P., Walker, T.S., Stermitz, F.R., Hufbauer, R.A., Vivanco, J.M. Enantiomeric dependent phytotoxic and antimicrobial activity of (1)-catechin; a rhizosecreted racemic mixture from Centaurea maculosa (spotted knapweed). Plant Physiology 128: 1173-1179, 2002. Bais, H.P., Vepachedu, R., Gilroy, S., Vivanco, J.M. A plant invasion process mediated by root allelochemicals: ecological, physiological, signal transduction and genomics evidence. In preparation for Science, 2002. Bais, H.P., park, S-W, Halligan, D.M., Stermitz, F.R., Vivanco, J.M. Exudation of fluorescent _-carbolines from Oxalis tuberosa L. roots. Phytochemistry (in press). Morel, C., Stermitz, F.R., Tegos, G., Lewis, K. Submitted to J. Nat. Prod., 2002. IDAHO Exon, J.H., South, E.H. Effects of sphingomyelin on aberrant colonic crypt foci development, colon crypt cell proliferation and immune function in an aging rat tumor model. Food and Chemical Toxicology (in press), 2002. ILLINOIS Santell, R.C., Kieu, N. Helferich, W.G. The phytoestrogen genistin inhibits growth of estrogen-independent human breast cancer cell growth in vitro but not in vivo. J. of Nutrition 130;1665-1669, 2000. Ju, Y.H., Carson, K., Katzenellenbogen, J., Sun, J., Choi, I.H., Katzenellenbogen, B, Helferich, W.G. Estrogenic effects of extracts from cabbage, fermented cabbage, and acidified brussel sprouts on growth of estrogen-dependent (MCF-7) and -independent (MDA 231) human breast cancer cells. J. Agric. Food Chem. 48: 4628-4634, 2000. Allred, C.D., Allred, K.F., Ju, Y., Virant, S.M., Helferich, W.G. Soy diets containing genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose dependent manner. Cancer Research 61;5045-5050, 2001. Allred, C.D., Ju, Y., Allred, K.F., Chang, J., Helferich, W.G. Dietary genistein stimulates growth of estrogen-dependent breast cancer tumors similar to that observed with dietary genistein. Carcinogenesis, 22: 1667-1673, 2001. Ju, Y-H, Allred, C.D., Allred, K.F., Karko, K.L., Helferich, W.G. Dose-response study of soy isoflavone, genistein, at physiological concentration range on the growth of estrogen-dependent human breast cancer (MCF-7) tumor implanted in athymic nude mice. Journal of Nutrition, 131 (11)2957-2962, 2001. Ju, Y-H, Doerge, C.D., Allred, D.R., Allred, K.F., Helferich, W.G. Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) in vivo. Cancer Research 62:2472-2477, 2002. Yellayi, S., Naaz, A., Szewczykowski, M.A., Sato, T., Woods, J.A., Chang, J., Segre, M., Helferich, W.G., Cooke, P.S. The soy phytoestrogen genistein induces thymic and immune abnormalities in mice: a potential human health hazard? Proc. Natl. Acad. Sci. 99:7616-7621, 200X. Hilakivi-Clarke, L., Cho, E., Cabanes, A., DeAssis, S., Olivo, S., Helferich, W.G., Kuoonab, M.E., Clarke, R. Modulation of pregnancy estrogen levels by maternal dietary exposure to soy isolate or n-3 polyunsaturated fatty acid and breast cancer risk among female rat offspring. J. Clinical Cancer Research (in press), 200X. Yellayi, S., Zakroczymski, M., Selvaraj, V., Valli, V.E., Ghanta, V., Helferich, W.G., Cooke, P.S. The phytoestrogen genistein suppresses cell-mediated immunity in mice. J. Endocrinology (in press), 2002. Helferich, W.G., Allred, C.D., Ju, Y-H., Dietary estrogens and anti-estrogens. In: Food Toxicology, W.G. Helferich and C.K. Winter, eds., CRC Press, Boca Rotan, FL. , 2001. Helferich, W.G. Effect of genistein on growth of human breast cancer cells in vitro and in vivo. In: Phytochemicals: A New Health Paradigm. Edited by Wayne Bidlack, 2000. MICHIGAN Yang, G-H., Pestka, J. Vomitoxin (deoxynivalenol) -mediated inhibition of nuclear protein binding to NRE-A, an IL-2 promoter negative regulatory element, in EL-4 cells. Toxicology, 172:169-179, 2002. Wong, S.S., Zhou, H-R., Pestka, J.J. Effects of vomitoxin (deoxynivalenol) on the binding of transcription factors AP-1, NF-kB and NF-IL6 in raw 264.7 macrophage cells. J. Toxicol.Environ. Health. 65:1161-1180, 2002. Pestka, J.J., Zhou, H-R., Jia, Q., Timmer, A.M. Dietary fish oil suppresses experimental IgA nephropathy in mice. J. Nutrition, 261-269, 2002. Islam, Z. Moon, Y.S., Zhou, H-R., King, L.E., Fraker, P.J., Pestka, J.J. Endotoxin potentiation of trichothecene-induced lymphocyte apoptosis is mediated by up-regulation of glucocorticoids. Toxicol. Appl. Pharmacol. 180: 43-55, 2002. Christensen, H.R., Frokiaer, H., Pestka, J.J. Lactobacilli differentially modulate expression of cytokines and maturation surface markers in murine dendritic cells. J. Immunol., 168 (1): 171-178, 2002. Sugita-Konishi, Y., Pestka, J.J. Differential up-regulation of TNF-alpha, IL-6, and IL-8 production by deoxynivalenol (vomitoxin) and other 8-ketotrichothecenes in a human macrophage model. J. Toxicol. Environ Health A. 64(8): 619-636, 2001. Zielinski, T.L., Smith, S.A., Pestka, J.J., Gray, J.I., Smith, D.M. ELISA to quantify hexanal-protein adducts in a meat model system. J. Agric. Food Chem. 49(6): 3017-3023, 2001. Wong, S.S., Schwartz, R.C., Pestka, J.J. Superinduction of TNF-a and IL-6 in macrophages by vomitoxin (deoxynivalenol) modulated by mRNA stabilization. Toxicology 161:139-149, 2001. Lee, M-G. Yuan, Q-P., Hart, L.P., Pestka, J.J. Enzyme-linked immunosorbent assays of zearalenone using polyclonal monoclonal and recombinant antibodies. In: M. Trucksess and A.E. Pohland (eds.), Mycotoxin Protocols, Methods in Molecular Biology, Vol. 157: 159-170, Human Press, Totowa, NJ., 2001. Pestka, J.J., Ha, C.L., Warner, R.W., Lee, J.H., Ustunol, Z. Effects of ingestion of yogurts containing Bifidobacterium and Lactobacillus acidophilus on spleen and Peyer‘s patch lymphocyte populations in the mouse. J. Food Prot. 64: 392-395, 2001 Zhou, H-R., Lau, A.S., Pestka, J.J. An essential role of double-stranded RNA-activated protein kinase PDR in vomitoxin-induced apoptosis in raw 264.7 cells. 41st Society of Toxicology Annual Meeting, Nashville, TN, 2002. Islam, Z., King, L.E., Fraker, P.J., Pestka, J.J. Differential induction of apoptosis in murine lymphoid subpopulations in vivo following co-exposure to lipopolysaccharide and vomitoxin. 41st Society of Toxicology Annual Meeting, Nashville, TN, 2002. Jia, Q., Pestka, J.J. Dietary fish oil suppresses vomitoxin-induced IgA nephropathy in the mouse. 41st Society of Toxicology Annual Meeting, Nashville, TN, 2002. Islam, Z., King, L.E., Fraker, P.J., Pestka, J.J. Differential induction of apoptosis in murine lymphoid subpopulations in vivo following co-exposure to lipopolysaccharide and vomitoxin. 41st Society of Toxicology Annual Meeting, Nashville, TN, 2002. Moon, Y., Pestka, J.J. Relationship of trichothecene structure to Cox-2 induction in the macrophage model. 41st Society of Toxicology Annual Meeting, Nashville, TN, 2002. Chung, Y., Pestka, J.J. Enhancement of TNF alpha-mRNA stability by deoxynivalenol through the activation of p38 kinase. 41st Society of Toxicology Annual Meeting, Nashville, TN, 2002. Pestka, J.J., Chung, Y., Jarvis, B.B., Tak, H. Development of antibodies to satratoxins and application to enzyme-linked immunosorbent assay. 41st Society of Toxicology Annual Meeting, Nashville, TN, 2002. OREGON Egner, P., Bailey, G., Groopman, J., Kensler, T. Chlorphyllin reduces urinary levels of a carcinogen-DNA adduct biomarker in residents of Qidong, People‘s Republic of China in a randomized, double-blind, placebo-controlled trial. Proc. Natl. Acad. Sciences, USA, 98:14601-14606, 2001. Stoner, G., Casto, B., Ralston, S., Roebuck, B., Pereira, C., Bailey, G. Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol. Carcinogenesis 23:265-272, 2002. Loveland, P., Reddy, A., Pereira, C., Field, J., Bailey, G. Application of matrix solid-phase dispersion in the determination of dibenzo (a, 1) pyrene content of experimental animal diets used in a large-scale tumor study. J. Chromatog. A. 932:33-41, 2001. UTAH Van Vleet, T.R., Bombick, D.W., Coulombe, Jr., R.A. Inhibition of human cytochrome P450 2E1 activity by nicotine, cotinine, and aqueous cigarette tar extract in vitro. Toxicological Sciences 64, 185-19, 2001. Coulombe, R.A. Antioxidants protect turkeys against toxicity of aflatoxin. NRI Research Highlights, National Research Initiative Competitive Grants Program, United States Department of Agriculture, Cooperative State Research, Education and Extension Service. No. 6, 2001. Van Vleet, T.R., Klein, P.J., Coulombe, Jr., R.A, Metabolism of aflatoxin B1 by normal human bronchial epithelial cells. J. Toxicology and Environmental Health, Part A, 63:101-116, 2001. Van Vleet, T.R., Maci, K., Coulombe, Jr., R.A. Comparative aflatoxin B1 activation and cytotoxicity in human bronchial cells expressing human CYPs 1A2 and 3A4. Cancer Research 62, 105-112, 2002. Van Vleet, T.R., Klein, P.J., Coulombe, Jr., R.A. Metabolism and cytotoxicity of aflaltoxin B1 in cytochrome P-450-expressing human lung cells. J. Toxicology and Environmental Health, Part A 65: 853-67, 2002. Klein, P.J., Van Vleet, T.R., Hall, J.O., Coulombe, Jr., R.A. Dietary butylated hydroxytoluene protects against aflatoxicosis in turkeys. Toxicology and Applied Pharmacology 182, 11-19, 2002. Klein, P.J., Van Vleet, T.R., Hall J.O., Coulombe, Jr., R. A. Biochemical factors underlying the age-related sensitivity of turkeys to aflatoxin B1. Comparative Biochemistry and Physiology, 132: 193-201, 2002. Klein, P.J., Van Vleet, T.R., Hall, J.O., Coulombe, Jr., R.A. Effect of dietary butylated hydroxytoluene on aflatoxin B1-relevant metabolic enzymes in turkeys. Food and Chemical Toxicology (in press), 2002. Van Vleet, T.R., Coulombe, Jr., R.A. Aflatoxin B1 alters expression of P43 in human lung cells. Toxicological Sciences (in press), 2002. Klein, P.J., Hall, J.O., Coulombe, Jr., R.A. Dietary butylated hydroxytoluene protects against aflatoxicosis in turkeys, In: T. Acamovic, C.S. Stewart and T.W. Pennycott (eds.) Poisonous Plants and Related Toxins, CAB International, London (in press), 2002. Coulombe, R.A., Rieben, W.K. Lack of apparent base sequence preference of activated pyrrolizidine alkaloid cross-links with DNA, In: T. Acamovic, C.S. Stewart and T.W. Pennycott (eds.) Poisonous Plants and Related Toxins, CAB International, London (in press), 2002. WRRC Brandon, D.L., Friedman, M. Immunoassays of soy proteins. J. Agric. Food Chem. 50: 6635-6642, 2002. Brandon, D.L., Bates, A.H., Binder, R.G., Montague, W.C.,Jr., Whitehand, L.C., Barker, S.A. analysis of fenbendazole residues in bovine milk by ELISA. J. Agric. Food Chem. 50: 5791-5796, 2002. Friedman, M., Henika, P.R., Mandrell, R.E. Bactericidal activities of plant essential oils and some of their isolated constituents against Escherichia coli, Salmonella enterica, Campylobacter jejuni, and Listeria monocytogenes. J. Food Protection 65: 1545-1560, 2002. Friedman, M. Tomato glycoalkaloids: role in the plant and in the diet. J. Agric. Food Chem. 50: 5751-5780, 2002. Friedman, M., Henika, P.R., Mackey, B.E. Effect of feeding solanidine, solasodine and tomatidine to non-pregnant and pregnant mice. Food Chem. Toxicol. (in press), 2002. Johnsson, L., Baxter, G.A., Crooks, S.R.H., Brandon, D.L., Elliott, C.T.E. Reduction of sample matrix effects-the analysis of benzimidazole residues in serum by immunobiosensor. Food Agric. Immunol. (in press), 2002. Kozukue, N., Friedman, M. Tomatine, chlorophyll, _-carotene, and lycopene contents in tomatoes during growth and maturation. J. Sci. Food Agric. (in press), 2003. Mandrell, R.E., Bates, A.H., Brandon, D.L. Monoclonal antibodies against Campylobacter jejuni and Campylobacter coli outer membrane antigens. U.S. Patent No. 6,395,879. 2002.

Impact Statements

The major indole-3-carbinol product, 3,3'-diindolymethane (DIM) is a novel and potent ligand-independent activator of the estrogen receptor in endometrial cancer cells that functions by initiating cross-talk between two kinase pathways and the estrogen receptor. DIM inhibits androgen activity in prostate tumor cells by competitively binding to the androgen receptor and preventing its translocation to the nucleus.
It is possible that compounds present in high abundance in soy and dietary supplements may stimulate growth of estrogen-dependent breast cancer by individuals that consume significant quantities of the dietary isoflavones.
Studies of Hypericum perforatum L., commonly known as St. John's wort, were conducted to develop an in vitro cell culture system for producing the plant and large quantities of its primary pharmacological agent hypericin. Hypericin levels were increased following exposure to jasmonic acid, and a major gene encoding for hypericin biosynthesis was cloned and characterized. These studies may provide researchers access to appropriate quantities of hypericin to allow its pharmacological properties
Traditional studies of the fungicidal activity of metalaxyl on F. moniliforme that investigate fungal survival may have led researchers to conclude that metalaxyl is not particularly effective, but from a food safety perspective, the reduction in fumonisin levels could be highly beneficial.
Fish oil can block DON-induced IgA dysregulation, providing insight into specific mechanisms by which omega-e fatty acids can block IgAN as well as other autoimmune and inflammatory disease processes. From a practical standpoint, the model may help answer questions about which omega-3s are most effective, the optimal dose regimens and omega-3 to omega-6 ratios, as well as the duration and frequency of omega-3s to get maximum benefit in treating overactive IgA responses and, perhaps, ultimately
CHL continues to show promise as a useful agent for prevention of cancer by at least three common classes of known or suspect human carcinogens - AFB1, heterocyclic amines, and polyaromatic hydrocarbons. The utility of natural chlorophylls, however, remains to be established. The mouse studies add to the growing evidence that tea components may be important dietary factors for the reduction of colon cancer risk
Finding chemoprevention strategies in domestic food animals such as poultry will help American agriculture produce a safer product for consumers
Initial efforts to amplify the trout 2K1 CYP and place it in Agrobacterium is the first step in transforming maize shoot cultures with this AFB1-detoxifying enzyme. Developing a transgenic corn that can detoxify its own AFB1 will help agriculture produce a safer food product.

Date of Annual Report: 08/23/2004

Report Information

Annual Meeting Dates: 10/09/2003 - 10/10/2003
Period the Report Covers: 10/01/2002 - 10/01/2003

Participants

Participants Attachment:

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Brief Summary of Minutes

Minutes Attachment:

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Accomplishments

Interdependent research amongst W-1122 researchers have made considerable progress toward our stated objectives -- identifying and determining the risk associated with food-borne toxins and carcinogens, determining their mode(s) of action, and discovering natural and synthetic bioactive chemoprotective agents to protect human health. This year, a digestive condensation product of cruciferous vegetables, DIM, was shown to inhibit several biochemical processes involved in the later stages of prostate tumor development. Root exudates were identified as having potent activity in breast tumor cells. Production of the carcinogenic mycotoxin fumonisin was shown to be inhibited by the fungicide metalaxyl in the corn meal. Several naturally occurring chemicals found in popular herbal supplements were shown to inhibit proinflammatory cytokine expression by the bacterial endotoxin in cell culture and mice. Two dozen compounds were found to be bactericidal against the food-borne pathogens Campylobacter jejuni, Escherichia coli O157:H7, Listeria monocytogenes, and Salmonella enterica. Natural and synthetic antioxidants were found to be powerful chemopreventive agents against aflatoxicosis in poultry. These and other collaborative research projects will continue in the coming year.

Publications

Publications Attachment:

Attachment

Impact Statements

Results of our studies of DIM in prostate tumor cells suggest that DIM inhibits several biochemical processes involved in the later stages of prostate tumor development
Our finding that certain antioxidants prevent toxic reponses in poultry will help American agriculture produce a safer product for consumers
Our aging population is increasingly developing inflammatory diseases like arthritis, allergy, lupus and nephropathy. The studies on herbal supplements and omega-3 fatty acids will assist in the development of foods and supplements that inhibit and delay these inflammatory diseases. This will lead to improvement in the quality of life of such affected individuals.
Results of our toxicological studies were used to set FDA guidelines and provisional maximal tolerable daily intakes (PMTDI) by the WHO/FAO.
We have identified chlorophyl as a powerful cancer-protective agent in a human intervention trial in China; its use worldwide as a cancer-preventive agent may be a possible step.

Date of Annual Report: 10/25/2004

Report Information

Annual Meeting Dates: 10/07/2004 - 10/08/2004
Period the Report Covers: 11/01/2003 - 10/01/2004

Participants

Administrative Advisor Michael Harrington (Colorado State), committee members George Bailey (Oregon), Len Bjeldanes (UCBerkeley), Roger Coulombe (Utah), Mendel Friedman (USDA-WRRC Albany, CA), Bill Helferich (Illinois), Bernadene Magnuson (Maryland), Jim Pestka (Micigan State), Ron Riley (USDA-ARS Athens, GA), Frank Stermitz (Colorado State), and Carl Winter (UCDavis).

Brief Summary of Minutes

Accomplishments

OBJECTIVE 1. Determine the cellular and molecular modes of action by which bioactive chemicals in food protect against human diseases such as cancer, inflammation and microbial infection. Chlorophyll and the synthetic derivative chlorophyllin were shown to have cancer protective properties which are related to inhibition of the environmental carcinogens dibenzopyrene and aflatoxin. Chlorophyll and chlorophyllin reduce access of the carcinogens to the liver, but complexation with the carcinogengs is not necessary for this activity. (Oregon). Tomatine, an alkaloid present in tomatoes, was shown to be nontoxic at high levels in a model using trout and hence the model will be useful for long-term studies to determine whether or not it can cause tumor formation or progression. (Oregon; USDA Albany, California). Dietary butylated hydroxytoluene (BHT) protects turkeys against aflatoxicosis caused by aflatoxins. This was shown to be due to inhibition of a consumed aflatoxin to its more toxic epoxide form (Utah State). Extracts of pigmented rice brans were found to be much stronger inhibitors of tumor promotion in marmoset cells than was an extract from nonpigmented white rice cooking varieties (USDA Albany). Green tea catechins, particularly epicatechin gallate, were shown to have potent antibactericidal activity against Bacillus cereus, a close model for Bacillus anthraxis (USDAAlbany). Anthocyanin-rich extracts of bilberry, grape and chokeberry significantly inhibited the growth of human colon cancer cell lines in vitro and also reduced aberrant crypt foci (presumed cancer precursors) in rats (Maryland). Omega-3 fatty acids found in fish oil were effective at suppressing an experimental model of a common kidney disease nephropathy (Michigan State). OBJECTIVE 2. Determine cellular effects and molecular mechanisms of natural and induced toxicants in food for human risk assessment and disease prevention. Gene chips were developed to study the way the indole-3-carbinol dimer (DIM) acts as a tumor promoter in the trout model. The promotion was found to act through an estrogenic pathway and continued after stopping DIM treatment, thus indicating no requirement for chronic exposure. (Oregon) On the other hand, DIM proved to have immune activating and antiangiogenic activity which reduced some tumors in other animal models.(UCBerkeley) These results from two different laboratories emphasize the complex biological interactions which need to be considered with dietary supplements such as DIM. The sensitivity of human white blood cells to the mycotoxin deoxynivalenol (DON or vomitoxin) was found to correlate to presence of a protein kinase. Humans are 4-fold more sensitive to this kinase than are mice and DON sensitivity was found to vary among individuals, perhaps due to both genetic and non-genetic factors (Michigan State). OBJECTIVE 3. Detect and identify new natural or induced bioactive compounds in foods that have beneficial or adverse effects on human health. Analytical methods were developed for detection of sphinganine-1-phophate in serum of animals exposed to subtoxic doses of fumonisins. Studies characterized a new sphingoid base metabolite in renal cells treated with fumonisin and suggested that this sphingoid could play an important role in fumonisin-induced renal toxiicty.(USDA-ARS Georgia). Curcumin, the yellow-coloring pigment in turmeric, was found to inhibit biofilm formation and toxin production in Pseudomonas aeruginosa, which causes lung disease symptoms in cystic fibrosis. This is accomplished through inhibition of quorum sensing, a communication mechansim in the bacterium. Curcumin did not kill the bacteria, which remained alive, but were no longer capable of causing disease. OBJECTIVE 4. Ascertain how agricultural production an food processing may influence production/stability of natural bioactive chemicals. A survey of literature reports which attempted to compare the beneficial (detrimental) effects of organic vs. traditional agriculture in regard to human health was made. From a scientific viewpoint, few or none of the studies appeared to be conclusive and there was a significant lack of quantitative data which appropriately compared the different methods. (UCDavis). A comparison was made between minimally processed soy-based products consumed in Asian countries and more processed soys or pure isoflavones. The degree of soy flour processing affected the estrogenicity of products although all were compared to a constant level of the isoflavone genistein. Thus, refined products were more estrogenic than those which are minimally processed. The findings suggest that for postmenopausal women with estrogen-dependent breast cancer, the consumption of foods containing soy flour rather than refined products is more advisable (Illinois). Maize products utilized in a Guatamalen Central Highland community were analyzed for toxic fumonisns and were often found to exceed the maximal tolerable daily intake established by the WHO. Lowland corn, which is imported and used in the highlands, was found to be a source of greater fumonosin content than that grown locally. A mouse model for fumonisin risk assessment was developed (USDA Athens, Georgia). COLLABORATIVE PLANS FOR COMING YEAR Bjeldanes(UCBerkeley) and Bailey(Oregon) will continue to study DIM and its carcinogenic and anticarcinogenic properties. Bailey(Oregon) and Friedman(USDA-WRRC Albany) will study the possible antitumour effects of the tomato alkaloid tomatine. Pestka (Michigan State) and Coulombe (Utah) plan to determine immunotoxic endpoints in poultry exposed to aflatoxin. Magnuson (Maryland) and Vivanco (Utah State) will expand their studies on curcumin.

Publications

Haendel, M.A., F.A. Tilton, G.S. Bailey, and R.L. Tanguay (2004). Developmental toxicity of the dithiocarbamate pesticide sodium metam in zebrafish. Toxicol. Sci. 81(2):390-400. Blum, C.A., Xu, M., Orner, G.A., Diaz, G.D., Li, Q., Dashwood, W.M., Bailey, G.S. and Dashwood, R.H. (2003) Promotion versus suppression of rat colon carcinogenesis by chlorophyllin and chlorophyll: Modulation of apoptosis, cell proliferation, and B-catenin/Tcf signaling. Mutat. Res. 523-524:217-223. Zhang, J., Hsu, J.C., Kinseth, M.A., Bjeldanes, L.F. and Firestone, G.L. Indole-3-carbinol induces a G1 cell cycle arrest and inhibits prostate-specific antigen production in human LNCaP prostate carcinoma cells. Cancer 98: 2511-2520, 2003. Chatterji, U., Riby, J.E., Taniguchi, T., Bjeldanes, E.L., Bjeldanes, L.F.and Firestone, G.L. Indole-3-carbinol stimulates transcription of the interferon gamma receptor 1 gene and augments interferon responsiveness in human breast cancer cells. Carcinogenesis. 18: 291 302, 2003. Leong, H., Riby, J., Firestone, G.L. and Bjeldanes, L. F. Potent ligand-independent estrogen receptor activation by 3,3-diindolylmethane is mediated by cross-talk between the PKA and MAPK signaling pathways. J. Mol. Endo. 18: 291-302, 2004. Rieben, W.K., and Coulombe, R.A. (2004). DNA cross-linking by dehydromonocrotaline lacks apparent base sequence preference. Toxicological Sciences 80, 1-7. Coulombe, R.A. (2003) Pyrrolizidine alkaloids in foods. Advances in Food and Nutrition Research (S.L. Taylor, Ed.). Elsevier Science Ltd., Oxford, U.K. Volume 45, pp. 61-99. Coulombe, R.A., Klein, P.J. and J.O. Hall (2003). Butylated hydroxytoluene chemoprotection: Response to Williams. Toxicology and Applied Pharmacology 189:152. Klein, P.J. Van Vleet, T.R., Hall, J.O. and R. A. Coulombe, Jr. (2003). Effect of dietary buylated hydroxytoluene on aflatoxin B1-relevant metabolic enzymes in turkeys. Food and Chemical Toxicology 41:671-678. Klein, P.J., Hall, J.O. and R. A. Coulombe, Jr. (2003). Dietary butulated hydroxytoluene protects against aflatoxicosis in turkeys, in Poisonous Plants and Related Toxins (T. Acamovic, C.S. Stewart and T.W. Pennycott eds.), CAB International, London. pp. 478-483. Coulombe, R.A., and W. K. Rieben (2003). Lack of Base Sequence Preference of Activated Pyrrolizidine Alkaloid Cross-Links with DNA, in Poisonous Plants and Related Toxins, (T. Acamovic, C.S. Stewart and T.W. Pennycott eds.) CAB International, London. pp. 26-31. Brandon, D. L., Bates, A. H., and Fridman, M. Immunoassays of Bowman-Birk and Kunitz soybean inhibitors in infant formula. J. Food Sci. 69, 11-15, 2004. Friedman, M. Applications of the ninhydrin reaction for analysis of amino acids, peptides, and proteins to agricultural and biomedical sciences. J. Agric. Food Chem. 52, 385-406, 2004. Friedman, M. Effects of food processing. In: Encyclopedia of Grain Science, C. Wrigley, H. Corke and C. E. Walker, eds., Elsevier, Oxford, UK, Vol. 2, pp. 328-340, 2004. Friedman, M. Analysis of biologically active compounds in potatoes (Solanum tuberosum), tomatoes (Lycopersicon esculentum), and Jimson weed (Datura stramonium) seeds. J. Chromatography A, 1054/1-3, 141-153 (special issue devoted to food safety). Friedman, M., Buick, R., and Elliott, C. T. Antibacterial activities of naturally occurring compounds against antibiotic-resistant Bacillus cereus vegeative cells and spores, Escherichia coli, and Staphylococcus aureus. J. Food Protection 67, 1774-1778, 2004. Friedman, M., Henika, P. R., Levin, C. E., and Mandrell, R. E. Antibacterial activities of essential oils and their components against Escherichia coli O157:H7 and Salmonella enterica in apple juice. J. Agric. Food Chem. 52, 6042-6048, 2004, 2004. Han, J. S., Kozukue, N., Young, K. S., Lee, K. R., and Friedman, M. Distribution of ascorbic acid in potato tubers and in home-processed and commercial potato foods. J. Agric. Food Chem. 52, 6516-6521, 2004. Kozukue, N., Han, J. S., Lee, K. R., and Friedman, M. Dehydrotomatine content of tomatoes. J. Agric.Food Chem. 52, 2079-2083, 2004. Lee, K. R., Kozukue, N., Han, J. S., Park, J. H., Chang, E. Y., Baek, E. J., Chang, J. S., and Friedman, M. Glycoakaloids and metabolites inhibit the growth of human colon (HT29) and liver (HepG2) cancer cells. J. Agric. Food Chem. 52, 2832-2839, 2004. Cooke, P.S., Naaz, A., Heine, P.A., Zakroczymski, M.A., Saunders, PTK, Taylor, J.A., Eckel, R.H., Jensen, D.R., Helferich, W.G., and Lubahn, D.B. (2003) Effects of estrogen and phytoestrogen signaling throughestrogen receptor ER-_alpha and ER_-beta on adipose tissue in males and females. Progress in Obesity Research: 9, John Libbey and Co., Eastleigh, United Kingdom pp. 458-461. Allred, C.A., Allred, K.F., Ju, Y.H., Doerge, D.R., Schantz, S., Korol, D., and Helferich, W.G. (2004) Dietary genistein results in larger MNU-induced, estrogen-dependent mammary tumors following ovariectomy of Sprague-Dawley rats. Carcinogenesis 25:211-218. Muthyala, R.S., Ju, Y.H., Sheng, S., Williams, L.D., Doerge, D.R., Katzenellenbogen, B.S., Helferich, W.G., and Katzenellenbogen, J.A. (2004) Equol, a natural estrogenic metabolite from soy isoflavones: convenient synthesis and resolution of R- and S-equol and their biological activity through the estrogen receptors alpha and beta. Bioorganic & Medicinal Chemistry 12(6): 1559-1567. Ju, Y-H, C.D. Doerge, DR, Allred, K.F., Allred, C.D. and W.G. Helferich (2002) Dietary Genistein Negates the Inhibitory Effect of Tamoxifen on Growth of Estrogen-dependent Human Breast Cancer (MCF-7) In Vivo. Cancer Research 62:2472-2477 Yellayi S., A. Naaz, M.A. Szewczykowski, T. Sato, J.A. Woods, J. Chang, M. Segre, W.G. Helferich, and P.S. Cooke (2002)., The soy phytoestrogen genistein induces thymic and immune abnormalities in mice: a potential human health hazard? Proc. Natl. Acad. Sci. 99:7616-7621. Hilakivi-Clarke L., E. Cho, A. Cabanes, S. DeAssis, S. Olivo, W.G Helferich M.E. Kuoonab, and R.Clarke (2002) Modulation of pregnancy estrogen levels by maternal dietary exposure to soy isolate or n-3 polyunsaturated fatty acid and breast cancer risk among female rat offspring. J. Clinical Cancer Research 8:3601-3610. M. Malik, C. Zhao, N.W. Schoene, M.M. Giusti, M.P. Moyer, B.A. Magnuson. 2003 Anthocyanin-rich extract from Aronia meloncarpa E. induces a cell cycle block in colon cancer but not normal colonic cells. Nutrition and Cancer 46 (2): 186-196. Y. Kwon, M. Malik and B.A. Magnuson. 2004. Inhibition of colonic aberrant crypt foci by curcumin in rats is affected by age. Nutrition and Cancer 48 (1):37-43. M. Malik and B.A. Magnuson, 2004. Rapid method for identification of chemopreventive compounds using multiplex RT-PCR for cyclooxygenase mRNA expression. Cancer Detection and Prevention. 28(4): 277-282. Kinser, S., Q. Jia, M. Li, A. Laughter, P. Cornwell, J. C. Corton, and J. Pestka. 2004. Gene expression profiling in spleens of deoxynivalenol-exposed mice: immediate early genes as primary targets. J. Toxicol. Environ. Health A 67:1423-1441. Pestka, J. J., H. R. Zhou, Y. Moon, and Y. J. Chung. 2004. Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox. Toxicol. Lett. 153:61-73. Jia, Q., Y. Shi, M. B. Bennink, and J. J. Pestka. 2004. Docosahexaenoic acid and eicosapentaenoic acid, but not alpha-linolenic acid, suppress deoxynivalenol-induced experimental IgA nephropathy in mice. J. Nutr. 134:1353-1361. Gregory, L., J. J. Pestka, D. G. Dearborn, and T. G. Rand. 2004. Localization of satratoxin-G in Stachybotrys chartarum spores and spore-impacted mouse lung using immunocytochemistry. Toxicol. Pathol. 32:26-34. Uzarski, R. L. and J. J. Pestka. 2003. Comparative susceptibility of B cells with different lineages to cytotoxicity and apoptosis induction by translational inhibitors. J. Toxicol. Environ. Health A 66:2105-2118. Moon, Y. and J. J. Pestka. 2003. Deoxynivalenol-induced mitogen-activated protein kinase phosphorylation and IL-6 expression in mice suppressed by fish oil. J. Nutr. Biochem. 14:717-726. Chung, Y. J., H. R. Zhou, and J. J. Pestka. 2003. Transcriptional and posttranscriptional roles for p38 mitogen-activated protein kinase in upregulation of TNF-alpha expression by deoxynivalenol (vomitoxin). Toxicol. Appl. Pharmacol. 193:188-201. Uzarski, R. L., Z. Islam, and J. J. Pestka. 2003. Potentiation of trichothecene-induced leukocyte cytotoxicity and apoptosis by TNF-alpha and Fas activation. Chem. Biol. Interact. 146:105-119. Moon, Y., R. Uzarski, and J. J. Pestka. 2003. Relationship of trichothecene structure to COX-2 induction in the macrophage: selective action of type B (8-keto) trichothecenes. J. Toxicol. Environ. Health A 66:1967-1983. Islam, Z. and J. J. Pestka. 2003. Role of IL-1(beta) in endotoxin potentiation of deoxynivalenol-induced corticosterone response and leukocyte apoptosis in mice. Toxicol. Sci. 74:93-102. Zhou, H. R., A. S. Lau, and J. J. Pestka. 2003. Role of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response. Toxicol. Sci. 74:335-344. Pestka, J. J. 2003. Deoxynivalenol-induced IgA production and IgA nephropathy-aberrant mucosal immune response with systemic repercussions. Toxicol. Lett. 140-141:287-295. Bais, H.P., Park, S.W., Weir, T.L. Callaway, R.M., and Vivanco, J.M. (2004) How plants communicate using the underground information superhighway. Trends in Plant Science 9:26-32 Veluri, R., Weir, T.L., Bais, H.P., Stermitz, F.R., and Vivanco, J.M. (2004) Phytotoxic and antimicrobial activities of catechin derivatives. Journal of Agricultural and Food Chemistry 52:1077-1082 Bais, H.P., Fall, R, and Vivanco, J.M. (2004) Biocontrol efficiency of Bacillus subtilis (6051) against Pseudomonas syringae (DC3000) in Arabidopsis thaliana roots is facilitated by biofilm formation and surfactin production. Plant Physiology 134: 307-319 Park, S-W., Vepachedu, R., Owens, R.A., and Vivanco, J.M. (2004) The N-glycosidase activity of the ribosome-inactivating protein ME1 targets single-stranded regions of nucleic acids independent of sequence or structural motifs. Journal of Biological Chemistry 279: 34165-34174 Weir, T., Park, S-W., and Vivanco, J.M. (2004) Biochemical and physiological mechanisms mediated by allelochemicals. Current Opinion in Plant Biology 7:472-479 Walker, T.S., Bais, H.P., Déziel E., Schweizer H.P., Rahme L.G., Fall R., and Vivanco, J.M. (2004) Pseudomonas aeruginosa-plant root interactions: pathogenicity, biofilm formation and root exudation. Plant Physiology 134:320-331 Voss KA, Meredith FI, Bacon CW. 2003. Effect of baking and frying on the in vivo toxicity to rats of cornmeal containing fumonisins. Journal of Agricultural and Food Chemistry 51: 5546-51. Palencia, E. Torres, O., Hagler, W., Meredith, F..I., Williams, L. D., and Riley, R.T. 2003. Total fumonisins are reduced in tortillas using the traditional nixtamalization method of Mayan communities. Journal of Nutrition 133:3200-3203 Sharma RP, He Q, Johnson VJ, Voss KA. 2003. Increased expression of CD95-ligand and other apoptotic signaling factors by fumonisin B1, a hepatotoxic mycotoxin, in livers of mice lacking tumor necrosis alpha. Cytokine 24: 226-236. Marasas, W.F.O., Riley, R.T., Hendricks, K.A., Stevens, V.L., Sadler, T.W., Gelineau-van Waes, J., Missmer, S.A., Cabrera Valverde, J., Torres, O.L., Gelderblom, W., Allegood, J., Martínez de Figueroa, A.C., Maddox, J., Miller, J.D., Starr, L., Sullards, M.C., Roman Trigo, A.V., Voss, K.A., Wang, E., Merrill, A.H., Jr. 2004. Fumonisins disrupt sphingolipid metabolism, folate transport and development of neural crest cells in embryo culture and in vivo: A risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize? Journal of Nutrition. 134:711-716. Williams, L.D., Meredith, F.I., and Riley, R.T. 2004. Fumonisin-ortho-Phthalaldehyde derivative is stabilized at low temperature. Journal of Chromatography (B) 806: 311-314. Merrill, A.H., Jr., Wang, E., Liotta, D.C. and Riley, R.T. 2004. Method of altering sphingolipid metabolism and detecting fumonisin ingestion and contamination. US Patent no. 6,720,184 issued 3 April, 2004. Winter, C.K.: Exposure and dose-response modeling for food chemical risk assessment. In: R.H. Schmidt and G.E. Rodrick (eds.), Food Safety Handbook, Wiley-Interscience, Hoboken, NJ, ps. 73-88, 2003. Winter, C.K.: Pesticides and herbicides. Toxicology. In B.L. Caballero, L. Trugo, and P. Finglas (eds), Encyclopedia of Food Sciences and Nutrition, 2nd Edition, Academic Press, San Diego, ps. 4494-4501, 2003. Winter, C.K.: Surveillance for pesticide residues. In Watson, D.H., (ed.), Pesticide, veterinary and other residues in food. Woodhead Publishing, Cambridge, England, ps. 277-293 (2004).

Impact Statements

Chlorophyll and its derivative chlorophyllin, the additive BHT, and extracts of berries containing high levels of pigments were all found to exhibit properties which suggest they could play an important part as anticarcinogens. Green tea catechins may be useful for combatting anthrax-related infections and omega-3-fatty acids are effective in supressing a common kidney disease.
Lung infections from Pseudomonas aeruginosa are the source of debilitating lung infections in cystic fibrosis and the turmeric component curcumin is used in some case to ameliorate this effect. It was found that curcumin is an effective antiinfective against P. pseudomonas because it inhibits that bacterium from producing its toxins, even though the bacterium is not killed. This is a new way to treat the disease and may not result in bacterial resistanceto drugs.
Refined soy products were found to be more estrogenic than were minimally-processed soy products. Women with estrogen-dependent breast cancer who use soy products should therefore use the less processed varieties.

Date of Annual Report: 11/01/2005

Report Information

Annual Meeting Dates: 10/06/2005 - 10/07/2005
Period the Report Covers: 11/01/2004 - 10/01/2005

Participants

Brief Summary of Minutes

Report Information:
" Annual Meeting Dates: 10/06/05 to 10/07/05
" Period the Report Covers: 11/2004 to 10/2005

Participants:
" Administrative Advisor Michael Harrington (Colorado), committee members George Bailey (Oregon), Len Bjeldanes (UC Berkeley), Roger Coulombe (Utah), Mendel Friedman (USDA-WRRC Albany, CA), Bill Helferich (Illinois), Richard Heimsch (Idaho), Jim Pestka (Michigan State), Ron Riley (USDA-ARS Athens, GA), Jorge Vivanco (Colorado State)

Brief Summary of Minutes of Annual Meeting: W-1122: Beneficial and Adverse Effects of Natural, Bioactive Dietary Chemicals on Human Health and Food Safety

Annual meeting of the technical committee, October 6-7, 2005 SunRiver, OR

The annual meeting was called to order at 0830 Thursday morning, October 6th.

Advisor Michael Harrington provided a report on the current status of funding within USDA for FY 2006. He reported that in the President's budget Hatch funds had been proposed to be reduced 50% and then "zeroed out" for FY2007; however, funding was restored by the House and Senate and in some cases slightly increased. Discussion of future budgets included some proposed program cuts but slight increases in extension funding and funding of the NRI. It is envisioned that disbursing of Hatch funds in the future could become more competitive although the manner in which this would be implemented is currently unclear. There was considerable discussion about the development of "core values" intended to maintain and strengthen the existing network of state institutions. Energy policy and its impact on agriculture was also discussed.

After these initial items, the annual reports were given.

The regular business portion of the meeting commenced Friday morning at 1000. Monterey California was selected as the site for the 2006 meeting and it was agreed that because a new Project Plan Outline was due in January 2007 (with the final project due in July 2007), that the 2006 meeting would meet for an extra day. For 2006, Bill Helferich would serve as Secretary, Ron Riley as Vice President and George Bailey as President. The agreed days were 4, 5 and 6 October. It was also agreed that presentations at the 2006 meeting would be limited to 20 min so as to provide more time to develop the new project outline and to discuss the new objectives developed by the Rewrite Committee. It was also agreed that the Rewrite Committee would be comprised of Roger Coulombe (Chair), Jim Pestka (to collate information), Len Bjeldanes and a person to be selected from Oregon State University. The Rewrite Committee agreed to meet in August 2006 to develop the Revised Outline and new objectives to be presented at the 2006 meeting of W1122. The meeting was adjourned at around 1200 on 7 October.

Minutes Attachment:

Attachment

Accomplishments

OBJECTIVE 1. Determine the cellular and molecular modes of action by which bioactive chemicals in food protect against human diseases such as cancer, inflammation and microbial infection. Two tumor studies compared the cancer chemopreventive efficacy of natural chlorophyll (Chl) with its water soluble food dye derivative chlorophyllin (CHL). Both agents strongly blocked aflatoxin-induced liver and colon cancer in the rat, and dibenzo(a,l)pyrene-induced liver and stomach cancer in the trout.(Oregon). Pathogenic strains of Pseudomonas syringae, but not non-pathogenic strains, were shown to confer host immune defense response by down-regulating secretion of a battery of antimicrobial compounds by the roots of Arabidopsis thaliana. The root tips also cease growing, which is in stark contrast to the belief that plants are sessile organisms that cannot act to avoid contact with pathogens. (Colorado). Exposure to deoxynivalenol (DON), one of the most common trichothecene mycotoxins in cereal grain, induces expression of interleukin-6 (IL-6), a proinflammatory cytokine, in part by triggering binding of the transcription factor cAMP response element binding protein (CREB) to the IL-6 promoter. Mechanism studies indicate that DHA consumption attenuates IL-3 expression by suppressing CREB phosphorylation in the mouse peritoneal macrophage; this occurs by downregulating specific kinase activities but not by upregulating PP1 and PP2A activities. (Michigan State). Dietary butylated hydroxytoluene (BHT) protects against nearly all clinical signs of aflatoxicosis in turkeys, with concentrations as low as 100 ppm BHT protecting against some signs of aflatoxicosis. The turkey liver CYP 1A2 homologue that has AFB1-epoxidation activity was cloned, expressed, and found likely important in the extreme sensitivity of turkeys to aflatoxin B1. (Utah). A new sphingoid base metabolite was identified in renal cells treated with fumonisin B1, and may play an important role in fumonisin renal toxicity. Fumonisin-induced hepatotoxicity in mice was determined by gene expression analyses not to be mediated through peroxisome proliferator responsive pathways. LM/Bc mice were found in reproduction studies to be more sensitive to induction of NTD than CD1, apparently through fumonisin-induced disruption of sphingolipid metabolism in fetal liver in the sensitive strain. (USDA ARS Athens,GA). OBJECTIVE 2: Determine cellular effects and molecular mechanisms of natural and induced toxicants in food for human risk assessment and disease prevention. Gene expression effects of aflatoxin B1 exposure were examined by extracting RNA from tumorous and histologically normal adjacent tissue in rainbow trout liver, and conducting microarray analysis on a salmonid ToxGeneChip. Genes down-regulated at least 2-fold in hepatocellular carcinoma included genes involved in normal liver functioning, blood coagulation and leukocyte aggregation, and iron absorption, whereas up-regulated genes included cell proliferation, extracellular matrix, immunoregulation and acute phase response genes. These expression changes strongly resemble those reported in human and rodent hepatocellular carcinoma. (Oregon). Deoxynivalenol was hypothesized to interfere with the immune response to reovirus infection. Experiments suggested that DON transiently increased both severity of the reovirus infection and shedding in feces as well as elevated reovirus IgA responses. These effects corresponded to suppressed Th1 and enhanced Th2 cytokine expression. (Michigan). The green tea catechins ()-gallocatechin-3-gallate, ()-epigallocatechin-3-gallate, ()-catechin-3-gallate, ()-epicatechin-3-gallate, theaflavin-3, 3-digallate, theaflavin-3-gallate, and theaflavin-3-gallate were found to exhibit antimicrobial activities at nanomolar levels. Freshly prepared tea infusions were more active than day-old teas. Tea catechins without gallate side chains, gallic acid and the alkaloids caffeine and theobromine also present in teas, and herbal (chamomile, peppermint) teas which contain no flavonoids are all inactive (USDA-WRRC Albany, CA). OBJECTIVE 3. Detect and identify new natural or induced bioactive compounds in foods that have beneficial or adverse effects on human health. 3,3'-diindolymethane (DIM) was found to inhibit Ras signaling induced by VEGF and other growth factors, which interferes with its downstream biological effects necessary for angiogenesis. Further studies showed that DIM strongly inhibited DNA topoisomerase IIa in a supercoiled DNA relaxation assay and instantly blocked DNA synthesis and mitosis. These results identified a new mode of action for this intriguing dietary component that is clearly distinct from the mitogenic effects of tumor promoters on these cells. (UC Berkeley). An improved HPLC method was developed and used to quantify capsaicin, dihydrocapsaicin, homocapsaicin-I, homocapsaicin-II, homodihydrocapsaicin-I, homodihydrocapsaicin-II, nonivamide, and nordihydrocapsaicin levels in parts of the pepper fruit (pericarp, placenta, seeds and in the top, middle, and base parts of whole peppers), in 17 species of peppers, and in 23 pepper-containing foods. (USDA-WRRC Albany, CA). OBJECTIVE 4. Ascertain how agricultural production and food processing may influence production/stability of natural bioactive chemicals. Baking cookies and crackers was found not to appreciable destroy DON, but it was degraded or otherwise "lost" during the frying of donuts. Maize samples from highland (> 1700 m) areas in Guatemala were found to be far less contaminated with fumonisin than lowland samples, where NTD incidence is often very high (USDA-ARS Athens, GA). OBJECTIVE 5. Identify and investigate modes of action of food-borne factors which may reduce the impact of dietary carcinogens. A preclinical mouse model was used to show that the soy phytochemical genestein acts in an additive manner with estrogen to stimulate growth of MCF-7 tumor growth in athymic mice. Daidzein was less effective, and its bacterial metabolite equal was ineffective in this model. (Illinois). The potato glycoalkaloids a-chaconine and a-solanine were purified and evaluated in a tetrazolium microculture (MTT) assay to assess anticarcinogenic effects. All samples tested reduced the numbers of the following human cell lines: cervical (HeLa), liver (HepG2), lymphoma (U937), stomach (AGS and KATO III) cancer cells and normal liver (HeLa Chang) cells. The results show that (a) the effects were concentration dependent in the range 0.1 to 10 mg/mL; (b) a-chaconine was more active than was a-solanine; (c) some mixtures exhibited synergistic effects; (d) the different cancer cells varied in their susceptibilities to destruction; and (e) the destruction of normal liver cells was lower than that of cancer liver cells.

Publications

Park S-W, Prithiviraj B, Vepachedu R and Vivanco JM 2005. Isolation and purification of ribosome-inactivating proteins. In Plant Tissue Culture Protocols. V. M. Loyola-Vargas and F. A. Vázquez-Flota, eds. Humana Press, Totowa, New Jersey, 335 347 Prithiviraj B, Bais HP, Weir T, Suresh B, Najarro EH, Dayakar BV, Schweizer HP, and Vivanco JM 2005. Salicylic acid down regulates virulence factors of Pseudomonas aeruginosa thereby attenuating its virulence on Arabidopsis thaliana and Caenorhabiditis elegans. Infection and Immunity 73:5319-5328 Horiuchi J, Prithiviraj P, Bais H.P, Kimball BA, and Vivanco JM 2005. Soil nematodes mediate positive interactions between legume plants and rhizobium bacteria. Planta DOI: 10.1007/s00425-005-0025-y Hompesch RW, Garcia CD, Weiss DJ, Vivanco JM, and Henry CS 2005. Analysis of natural flavonoids by microchip-micellar electrokinetic chromatography with pulsed amperometric detection. The Analyst 130:694-700. Callaway RM, Ridenour WM, Laboski T, Weir T, and Vivanco JM 2005. Natural selection for resistance to the allelopathic effects of invasive plants. Journal of Ecology 93:576-583 Prithiviraj B, Bais HP, Jha AK, and Vivanco JM 2005. Staphylococcus aureus pathogenicity on Arabidopsis thaliana is mediated either by a direct effect of salicylic acid on the pathogen or by SA-dependent, NPR1 independent host responses. Plant Journal 42:417-432 Bais HP, Prithiviraj B, Jha AK, Ausubel FM, and Vivanco JM 2005. Root exudation of antimicrobials mediates pathogen resistance. Nature 434:217-221 Vepachedu R, Park S-W, Sharma N, and Vivanco JM 2005. Bacterial expression and enzymatic activity analysis of ME1, a ribosome-inactivating protein from Mirabilis expansa. Protein Expression and Purification 40:142-151 Vivanco JM, Cosio E, Loyola-Vargas VM, and Flores HE 2005. Los mecanismos quimicos de defensa en las plantas. Investigación y Ciencia [Scientific American Latinoamerica] 341:68-75 Prithiviraj B, Weir T, Bais HP, Schweizer HP and Vivanco JM 2005. Plant models for animal pathogenesis. Cellular Microbiology 7:315-324 Thelen GC, Vivanco JM, Newingham B, Good W, Bais HP, Landres P, Caesar A and Callaway RM 2005. Insect herbivory stimulates allelopathic exudation by an invasive plant and the suppression of natives. Ecology Letters 8:209-217 Jha AK, Bais HP and Vivanco JM 2005. Enterococcus faecalis uses mammalian virulence-related factors to exhibit potent pathogenicity in the Arabidopsis thaliana plant model. Infection and Immunity 73:464-475 Friedman M and Mottram DS (Editors) 2005. Chemistry and Safety of Acrylamide in Food, Springer, New York; Advances in Experimental Medicine and Biology, Volume 561 Friedman M 2005. Biological effects of Maillard browning products in relation to safety of acrylamide. Advances in Experimental Medicine and Biology 561, 135-156 Friedman M, Lee K R, Kim HJ, Lee IS and Kozukue N 2005. Anticarcinogenic effects of glycoakaloids from potatoes against human cervical, liver, lymphoma, and stomach cancer cells. Journal of Agricultural and Food Chemistry 53, 6162-6169 Nam SH, Choi SP, Kang MY, Kozukue N and Friedman M 2005. Antioxidative, antimutagenic, and anticarcinogenic activities of rice bran extracts in chemical and cell assays. Journal of Agricultural and Food Chemistry 53, 816-822 Nam SH, Choi SP, Kang MY, Koh H J, Kozukue N and Friedman M 2005. Bran extracts from pigmented rice seeds inhibit tumor promotion in lymphoblastoid B cells by phorbol ester. Food and Chemical Toxicology 43, 741-745 Cousin MA, Riley RT and Pestka JJ 2005. Foodborne mycotoxins: Chemistry, biology, ecology, and toxicology. in "Foodborne Pathogens: Microbiology and Molecular Biology". Pp 164-226. P. M. Fratamico and A. K. Bhunia (ed) Horizon Scientific Press, Ltd., Norfolk, UK. Riley RT and Pestka J 2005. Mycotoxins: metabolism, mechanisms and biochemical markers. In "The Mycotoxin Blue Book" Duarte Diaz, Ed., pp 279-294. Nottingham University Press, Nottingham, UK. Rentz SS, Meredith FI, Showker JA and Riley RT 2005. Inhibition of Sphingolipid Biosynthesis Decreases Phosphorylated ERK2 in LLC-PK1 Cells. Food and Chemical Toxicology. 43: 123-131 He Q, Riley RT, and Sharma RP 2005. Myriocin prevents fumonisin B1-induced sphingoid base accumulation in mice liver without ameliorating hepatotoxicity. Food and Chemical Toxicology 43:969-979 Gelineau-van Waes J, Starr L, Maddox JR, Aleman F, Voss KA, Wilberding J and Riley RT 2005. Maternal fumonisin exposure and risk for neural tube defects: Disruption of sphingolipid metabolism and folate transport in an in vivo mouse model. Birth Defects Research (A) 73: 487-497 Piva A, Casadei G, Pagliuca G, Cabassi E, Galvano F, Solfrizzo M, Riley RT and Diaz DE 2005. Inability of activated carbon to prevent the toxicity of culture material containing fumonisin B1 when fed to weaned piglets Journal of Animal Science 83: 1939-1947 Stauber AJ, Brown-Borg H, Liu J, Waalkes MP, Laughter A, Staben RA, Coley JC, Swanson C, Voss KA, Kopchick JJ and Corton JC 2005. Constitutive expression of peroxisome proliferator-activated receptor alpha-regulated genes in dwarf mice. Molecular Pharmacology. 67: 681-694 Humpf H-U and Voss KA 2004. Effects of food processing on the chemical structure and toxicity of fumonisin mycotoxins.Molecular Nutrition and Food Research 48:255-269 Corton JC, Apte U, Anderson SP, Limaye P, Yoon L, Latendresse J, Dunn C, Everitt JI, Voss KA, Swanson C, Kimbrough C, Wong JS, Gill SS, Chandraratna RA, Kwak M, Kensler TW, Stulnig TM, Steffensen KR, Gustafsson JA, Mehendale HM. 2004. Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors. Journal of Biological Chemistry 279: 46204-46212 Voss KA, Riley RT, and Gelineau-van Waes J 2005. Trends in fumonisin research: Recent studies on the developmental effects of fumonisins and Fusarium verticillioides. Mycotoxins 55: 91-100 Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL and Bjeldanes LF 2004. Pilot study: effect of 3,3'-diindolylmethane (DIM) supplements on urinary hormone metabolites in postmenopausal women with a history of early stage breast cancer. Nutrition and Cancer 50(2): 161-167 Chang X, Tou JC, Hong C, Kim H-A, Riby J, Firestone GL and Bjeldanes LF 2005. 3,3-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice. Carcinogenesis 26(4): 771-778 Garcia HH, Brar GA, Nguyen DHH, Bjeldanes LF and Firestone GL 2005. Indole-3-carbinol (I3C) inhibits cyclin dependent kinase-2 function in human breast cancer cells by regulating the size distribution, associated cyclin E forms and subcellular localization of the CDK2 protein complex. J. Biol. Chem. 280(10): 8756-64 Xue L, Schaldach CM, Janosik T, Bergman J, and Bjeldanes LF 2005. Effects of analogs of indole-3-carbinol cyclic trimerization product in human breast cancer cells. Chem. Biol. Interact. 152(2-3): 119-29 Xue L, Firestone GL and Bjeldanes LF 2005. DIM stimulates IFNgamma gene expression in human breast cancer cells via the specific activation of JNK and p38 pathways. Oncogene. 24(14): 2343-53 Hsu JC, Zhang J, Dev A, Wing A, Bjeldanes LF. and Firestone GL 2005. Indole-3-carbinol inhibition of androgen receptor expression and down-regulation of androgen responsiveness in human prostate cancer cells. Carcinogenesis. 2005 Jun 15; [Epub ahead of print] Brew CT, Aronchik I, Hsu JC, Sheen JH, Dickson RB, Bjeldanes LF and Firestone GL 2005. Indole-3-carbinol activates the ATM signaling pathway independent of DNA damage to stabilize p53 and induce G1 arrest of human mammary epithelial cells. Int J Cancer. 2005 Sep 8; [Epub ahead of print] Coulombe RA, Guarisco JA, Klein PJ and Hall JO 2005. Chemoprevention of aflatoxicosis in poultry by dietary butylated hydroxytoluene. Animal Feed Science and Technology 121: 217-225 Yip SSM and Coulombe RA Jr. 2005. Molecular cloning and expression of a novel cytochrome P450 from turkey liver with aflatoxin B1 metabolizing activity. Chem. Res. Toxicol. (submitted for publication) Van Vleet TR, Watterson TL, Klein PJ and Coulombe RA, Jr. 2005. Aflatoxin B1 alters the expression of p53 in cytochrome P450-expressing human lung cells. Toxicological Sciences. (in press) Rieben WK and Coulombe RA 2004. DNA cross-linking by dehydromonocrotaline lacks apparent base sequence preference. Toxicological Sciences 82, 497-503 Islam Z and Pestka JJ 2005. LPS priming potentiates and prolongs proinflammatory cytokine response to the trichothecene deoxynivalenol in the mouse. Toxicol. Appl. Pharmacol. (in press) Smolinski AT and Pestka JJ 2005. Comparative effects of the herbal constituent parthenolide (Feverfew) on lipopolysaccharide-induced inflammatory gene expression in murine spleen and liver. J Inflamm. (Lond) 2, 6 Zhou HR, Islam Z and Pestka JJ 2005. Induction of competing apoptotic and survival signaling pathways in the macrophage by the ribotoxic trichothecene deoxynivalenol. Toxicol. Sci. 87(1), 113-122 Li M, Cuff CF and Pestka J 2005. Modulation of murine host response to enteric reovirus infection by the trichothecene deoxynivalenol. Toxicol. Sci. 87(1), 134-145 Urraca JL, ito-Pena E, Perez-Conde C, Moreno-Bondi MC and Pestka JJ 2005. Analysis of zearalenone in cereal and Swine feed samples using an automated flow-through immunosensor. J Agric. Food Chem. 53(9), 3338-3344 Jia Q and Pestka JJ 2005. Role of cyclooxygenase-2 in deoxynivalenol-induced immunoglobulin a nephropathy. Food Chem. Toxicol. 43(5), 721-728 Zhou HR, Jia Q and Pestka JJ 2005. Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. Toxicol. Sci. 85(2), 916-926 Pestka JJ and Smolinski AT 2005. Deoxynivalenol: toxicology and potential effects on humans. J Toxicol. Environ. Health B Crit Rev. 8(1), 39-69 Kinser S, Li M, Jia Q and Pestka JJ 2005. Truncated deoxynivalenol-induced splenic immediate early gene response in mice consuming (n-3) polyunsaturated fatty acids. J Nutr. Biochem. 16(2), 88-95 Pestka JJ, Uzarski RL and Islam Z 2005. Induction of apoptosis and cytokine production in the Jurkat human T cells by deoxynivalenol: role of mitogen-activated protein kinases and comparison to other 8-ketotrichothecenes. Toxicology 206 (2), 207-219 Allred CA, Allred KF, Ju YH, Doerge DR, Schantz S, Korol D and Helferich WG 2004. Dietary genistein results in larger MNU-induced, estrogen-dependent mammary tumors following ovariectomy of Sprague-Dawley rats. Carcinogenesis 25:211-218 Muthyala RS, Ju YH, Sheng S, Williams LD, Doerge DR, Katzenellenbogen BS, Helferich WG and Katzenellenbogen JA 2004. Equol, a natural estrogenic metabolite from soy isoflavones: convenient synthesis and resolution of R- and S-equol and their biological activity through the estrogen receptors alpha and beta. Bioorganic & Medicinal Chemistry 12(6): 1559-1567 Selvaraj V, Zakroczymski MA, Naaz A, Mukai M, Ju YH, Doerge DR, Katzenellenbogen JA, Helferich WG and Cooke PS 2004. Estrogenicity of the isoflavone metabolite equol on reproductive and non-reproductive organs in mice. Biology of Reproduction 71:966-972 Ju YH, Clausen LM, Almada AL and Helferich WG 2004. Beta$-sitosterol, $Beta-sitosterol glucoside, and a mixture of $Beta- sitosterol and $-sitosterol glucoside modulate the growth of estrogen-responsive breast cancer cells in vitro and in ovariectomized athymic mice. J. Nutr. (In Press) Allred CA, Allred KF, Ju YH, Doerge DR and Helferich WG 2004. Soy processing influences growth of estrogen-dependent breast cancer tumors. Carcinogenesis 25(9):1649-1657 Allred CD, Twaddle NC, Allred KF, Churchwell MI, Ju YH, Helferich WG and Doerge DR 200X. Soy processing affects metabolism and disposition of dietary isoflavones in ovariectomized Balb/c mice. J. Ag and Food Chem. (In Press) Ju YH, Fultz J, Allred KF, Doerge DR and Helferich WG 200X. Effects Of Dietary Daidzein And Its Metabolite, Equol, At Physiological Concentrations On The Growth Of Estrogen-Dependent Human Breast Cancer (MCF-7) Tumor Implanted In Ovariectomized Athymic Mice.Carcinogenesis(In Press) Tilton SC, Givan SA, Pereira C, Bailey GS and Williams DE 2005. Toxicogenomic profiling of the hepatic tumor promoters indole-3-carbinol, 17²-estradiol and ²-naphthoflavone in rainbow trout. Toxicol. Sci. Advanced Access Sept. 28, 2005. 10.1093/toxsci/kfi341 Tilton SC, Gerwick, LG, Hendricks JD, Rosato C, Corley-Smith G, Givan SA, Bailey GS, Bayne CJ and Williams DE 2005. Use of a rainbow trout oligonucleotide microarray to examine transcriptional patterns in aflatoxin B1-induced hepatocellular carcinoma compared to adjacent liver. Toxicol. Sci. Advanced Access Sept. 1, 2005. 10.1093/toxsci/kfi309

Impact Statements

Liver cancer is the third leading cause of cancer death worldwide, the most rapidly increasing cancer in the US. The finding for the first time that the natural phytochemical chlorophyll is highly effective at blocking liver cancer initiation in experimental animals has enormous implications for people in parts of Asia and Africa, where as many as 10% of adults may die of aflatoxin-related liver cancer by age 45. These studies were carried out by investigators at Oregon State University Agricultural Experiment Station. For additional information contact George Bailey (541/737-3164; george.bailey@oregonstate.edu)
Current understanding of plant immunity does not readily explain why a pathogen fully virulent on one crop species is non-pathogenic on another. Our recent results help unravel the immune mechanism, enabling researchers and producers to better understand plant infection and immunity. These studies were carried out by investigators at Colorado State University Agricultural Experiment Station. For additional information contact Jorge Vivanco (970-491-7019, jvivanco@lamar.colostate.edu
The finding that the soy isoflavone genestein acts additively with estrogen to stimulate estrogen-dependent tumor growth in the mouse raises doubts for its safety for postmenopausal women with estrogen-dependent breast cancer. These studies were carried out by investigators at University of Illinois. For additional information contact William Helferich 217-244-5414 helferic@uiuc.edu
The models developed from the DHA (omega-3 fatty acid) project will directly inform medical care workers on the applicability omega-3 fatty acid supplementation for prevention/treatment of IgAN and other diseases that involve inflammatory gene induction as well as omega-3 tissue levels and dosages. The trichothecene mechanism work will yield mechanism-based strategies for preventing and/or treating toxic effects in persons exposed to trichothecenes and ribotoxic chemicals in foods via natural contamination or as a result of deliberate use in chemical terrorism or warfare. This work was conducted by Dr. James Pestka at Michigan State University 517-353-1709 pestka@msu.edu.
Finding chemoprevention strategies in domestic food animals such as poultry will help American agriculture produce a safer product for consumers. This research was recently featured in the magazine Science Digest in March 2005 (http://www.sciencenews.org/articles/20050326/food.asp). This work was carried out at Utah State University Agricultural Experiment Station. For further information contact Dr. Roger Coulombe at 435-797-1598 rogerc@cc.usu.edu
New results indicate that DIM may inhibit blood supply development in growing tumors, as well as a general cytostatic effect on rapidly proliferating tumor cells. These could represent new applications of this supplement in cancer treatment, however additional animal studies are needed before these findings will have application. This work was carried out a UC Berkeley, by Dr. Leonard Bjeldanes, who may be reached at 510-642-1601 lfb@nature.berkeley.edu
Studies in the past year have improved the understanding of the mechanisms of fumonisin renal toxicity and NTD teratogenicity, which can guide risk assessment strategies. Field studies of regional maize contamination in Guatemala may provide a means to reduce human exposure to fumonisin throughout Central America. These studies were carried out at the USDA ARS in Athens, Georgia. For additional information contact Ronald T. Riley 706 546-3377 rriley@saa.ars.usda.gov
The surprising antimicrobial potency of tea extracts holds promise to reduce human microbial infections. Similarly, the reported toxic effects of potato glycoalkaloids may be balanced by potential beneficial effects including potentiation of the immune system and destruction of cancer cells. For further information contact Dr. Mendel Friedman at USDA WRRC, Albany, California mfried@pw.usda.gov

Date of Annual Report: 01/12/2007

Report Information

Annual Meeting Dates: 10/03/2006 - 10/06/2006
Period the Report Covers: 10/01/2002 - 09/01/2007

Participants

Administrative Advisor Michael Harrington (wdal@lamar.colostate.edu) - Colorado State University; George Bailey (george.bailey@oregonstate.edu) - Oregon State University; Len Bjeldanes (lfb@nature.berkeley.edu) - University of California, Berkeley; Roger Coulombe (rogerc@cc.usu.edu) - Utah State University; Mendel Friedman (mfried@pw.usda.gov) - USDA-WRRC Albany, CA; Bill Helferich (helferic@uiuc.edu) - University of Illinois; Jim Pestka (pestka@msu.edu) - Michigan State University; Ron Riley (ron.riley@ars.usda.gov) - USDA-ARS Athens, GA; Michael Denison (msdenison@ucdavis.edu) - University of California, Davis

Brief Summary of Minutes

Report Information:

- Annual Meeting Dates: 10/05/06 to 10/07/06

- Period the Report Covers: 10/2005 to 09/2006

Participants:

Administrative Advisor Michael Harrington (Colorado), committee members George Bailey (Oregon), Len Bjeldanes (UC Berkeley), Roger Coulombe (Utah), Mendel Friedman (USDA-WRRC Albany, CA), Bill Helferich (Illinois), Jim Pestka (Michigan State), Ron Riley (USDA-ARS Athens, GA), Michael Denison (University of California, Davis)

Brief Summary of Minutes of Annual Meeting:

W-1122: Beneficial and Adverse Effects of Natural, Bioactive Dietary Chemicals on Human Health and Food Safety

Annual meeting of the technical committee, October 5-7, 2006 Monterey, CA

The annual meeting was called to order at 0830 Thursday morning, October 5th, 2006.

Advisor Michael Harrington provided a report on the current status of funding within USDA for FY 2007. He reported that in the President's budget Hatch funds have the potential for significant change. These changes may include:

1. Making a portion of Hatch funds competitive

2. Create National Institutes of Food and Agriculture Research

3. Focus on problem-base areas like the NIH

These potential changes will require significant additional discussion. Further details of the potential changes can be found at www.create-21.org.

After Dr. Harrington's comments the annual reports were given as follows:

Technical Reports

Bailey, George - Oregon State University

Bjeldanes, Len - University of California at Berkeley

Coulombe, Roger - Utah State University

Pestka, Jim - Michigan State University

Helferich, Bill - University of Illinois

Friedman, Mendel - USDA-ARS Albany

Denison, Mike - University of California Davis

Riley, Ron - USDA-ARS Athens

Discussion on the revised new project plan for the next five years were discussed and changes were made to the draft document. Additional details will be added by Dr. Coulombe and will be sent directly to him at rogerc@cc.usu.edu. The W1122 project plan is due July, 2007.

The regular business portion of the meeting commenced Friday morning. Napa California was selected as the site for the 2007 meeting (October 3,4,,&5, 2007. For 2007, Mike Denison would serve as Secretary, Bill Helferich as Chair-elect and Ron Riley as Chair. The meeting was adjourned at around 1200 on October 6, 2006.

Accomplishments

ACCOMPLISHMENTS FOR THE ENTIRE SPAN OF THE PROJECT ARE SUMMARIZED BEGINNING WITH 2006 The activities described below have addressed specific components of the W1122 Multistate project as outlined in the milestones document for the project. Many of the activities have been collaborative efforts among W1122 participants and all have benefited from the critical review provided by all particpants at the annual meetings and throughout the year. Over the five year span of the project, the activities described below have been documented by over 300 publications and numerous reports and data provided to industry, consumers, and authorative bodies such as the USFDA, WHO/FAO, International Agency for Research on Cancer, Council for the Advancement of Science and Technology, etc. Participants from Oregon, Michigan, Utah, Berkeley and USDA-ARS have played leadership roles in the Society of Toxicology (SOT)and have organized symposia and workshops that have promulgated the W1122 message and activities at the annual meetings of SOT and other international societies and conferences including the Gordon Research Conferences. OBJECTIVE 1. Determine the cellular and molecular modes of action by which bioactive chemicals in food protect against human diseases such as cancer, inflammation and microbial infection. 2006 Continuing research to define the interrelationships between carcinogen (dibenzo(a,l)pyrene, DBP) dose, chlorophyll (Chl) dose, maximal target organ DNA adduction, and final tumor outcome was conducted by the group in Oregon. The results show that in liver at carcinogen doses and tumor levels relevant to human cancer rates, natural chlorophyll can provide potent inhibition of DBP tumorigenicity at dietary Chl concentrations well within the range found in spinach. These findings provides strong evidence for the beneficial effects of dietary CHl and will be useful to nutritionist and food safety scientists worldwide. A collaborative tumor study involving the W1122 team in Oregon and USDA-ARS - Albany showed that tomatine, a chemical found in tomato leaves, given during the period of carcinogen treatment, significantly inhibited tumor incidence in liver and stomach. This is an important finding that further demonstrates the importance of bioactive chemicals in foods. The group at Michigan conducted and published research showing that consumption of the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) suppressed activation of signaling processes that modulate inflammatory gene expression in macrophages. These findings are important because they provide insight for biomedical researchers into the mechanisms for PUFA suppression of proinflammatory cytokine expression. The group at USDA-ARS in Athens conducted and published the results of research activities that showed that the nephrotoxicity of fumonisins in rats is a result of the preferential accumulation of both fumonisins, and sphingoid bases and sphingoid base 1-phosphates. The results provide a plausible explanation for why rat kidney is so much more sensitive that rat liver to fumonisin toxicity. This finding is important because nephrotoxicity in rat is the critical effect used for establishing the current tolerable daily intake set by the WHO/FAO Joint Expert Committee on Food Additives. The group at USDA-ARS Athens has developed a model system for studying the mechanistic basis for Fusarium verticillioides-induced corn seedling desease and the role of fumonisins as virulence factors. The model may prove useful for developing a better understanding of the basis for seedling resistance to F. verticillioides. The Utah group cloned, expressed and characterized a turkey liver CYP 1A5 (1587 bp ; 528 amino acids) that has high AFB1-epoxidation activity, that may be responsible, at least in part, for the well-known hypersensitivity of turkeys to AFB1. This may be the first P450 cloned and sequenced from turkeys. These results provide the framework for identifying allelic variants of this biochemically important CYP gene in poultry and the basis for breeding for increased resistance to aflatoxins in farm raised turkeys. 2005 to 2002 Research activities by W1122 team members in Oregon included tumor studies comparing the cancer chemopreventive efficacy of natural chlorophyll (Chl) with its water soluble food dye derivative chlorophyllin (CHL). The research resulted in several key publications containing the information needed by risk managers to implement interventions to reduce liver cancer risk in high risk populations. Research activities by the group at Utah State University found that dietary butylated hydroxytoluene (BHT) protects against nearly all clinical signs of aflatoxicosis in turkeys, with concentrations as low as 100 ppm BHT protecting against some signs of aflatoxicosis. These findings were published and the information provides the basis for developing interventions to reduce the economic losses incurred by aflatoxin poisoning. Research activities by the group in Georgia in collaboration with researchers from the University of Nebraska found that neural tube defects could be induced in LM/Bc mice and that the mechanism of action involved disruption of the folate transporter. This information was published and filled an important gap in the fumonisin risk assessment conducted by the WHO/FAO Joint Expert Committee on Food Additives. The W1122 group in Oregon showed that chlorophyll and the synthetic derivative chlorophyllin had cancer protective properties which were related to inhibition of the environmental carcinogens dibenzopyrene and aflatoxin. A collaborative study between USDA-ARS Albany and the group in Oregon found that tomatine, an alkaloid present in tomatoes, was nontoxic at high levels using trout, paving the way for long-term studies on the efficacy of tomatine to modulate tumor formation or progression. The Utah State team found that dietary butylated hydroxytoluene (BHT) protects turkeys against aflatoxicosis and the mechanism appears to involve inhibition of epoxide formation. This work sets the stage for more in depth studies of BHT as a intervention strategy. USDA-ARS Albany found that extracts of pigmented rice brans were much stronger inhibitors of tumor promotion than extracts from nonpigmented white rice cooking varieties and studies on green tea catechins were shown to have potent antibactericidal activity. The W1122 group at Michigan State found that omega-3 fatty acids found in fish oil were effective at suppressing an experimental model of a common kidney disease. In an investigation by the group at Berkeley it was found that DIM stimulated the activity of an estrogen receptor- responsive reporter by up to 40 fold. The stimulatory effect was abolished with an estrogen receptor antagonist. In a separate study it was found that DIM is a potent antagonist of androgen function in prostate tumor cells. These findings show that DIM is a mechanistically novel activator of the estrogen receptor and establish DIM as a unique bifunctionally active hormone disruptor. W1122 researchers at Michigan found that the two main omega-3 polyunsaturated fatty acids in fish oil, docosahexaenoic acid and eicosapentaenoic acid, retard progression of primary IgA nephropathy and also significantly reduce IgA secretion by spleen cells in mice induced by the tricothecene mycotoxin deoxynivalenol (DON). They also showed that DON affects expression of multiple genes that may contribute to its immunotoxic effects and this expression profile can be affected by diets containing omega-3 fatty acids. In anticipation of future studies, researchers at Oregon assessed the dose-dose interactions between dietary chlorophyllin (CHL) and dibenzo(a,1)pyrene (DBP) in the trout multi-organ tumorigenesis model. Overall, CHL-mediated reduction in target organ DNA adduction was found to be a predictive biomarker for eventual reduction of tumor risk in both target organs (stomach and liver). In collaboration with Oregon researchers, the group at Utah initiated a study introducing an efficient AFB1 metabolizing enzyme into plants. The CYP isoform appears to be a "pure epoxidator" in that it forms no other non-epoxidated metabolites. Various CYP-containing gene cassettes are being expressed into E. coli and into Agrobacterium for later tranfection into tobacco and maize. OBJECTIVE 2. Determine cellular effects and molecular mechanisms of natural and induced toxicants in food for human risk assessment and disease prevention. 2006 Research conducted by the Oregon group used an IRB approved ultra-low dose 14C-AFB1 (5 nCi, 30 ng) (provided by USDA-ARS Athens) to assess AFB1 uptake, distribution, and elimination in humans. This study will provide the most complete pharmacokinetic analysis ever conducted for AFB1 in humans. It also has set the stage for examination of CHL and Chl effects on AFB1 bioavailability in humans, which is currently in progress. The group in Michigan continued their in depth probe to define the molecular mechanisms by which deoxynivalenol alters immune response. They found (i) deoxynivalenol (DON) activated competing apoptotic and survival pathways in macrophages and (ii) extremely rapid association and activation of PKR, Hck, ERK was detected in ribosomes from DON-treated RAW 264.7 cells. These observations suggest that, following DON interaction, signaling pathways are affected and that the ribosome functions as signal transducer and mediates activation and binding of a number of protein kinases These interactions can potentially affect transcriptional and translational regulation of cytokine and chemokine genes as well as apoptosis induced by DON. 2005 to 2002 Microarray studies in rainbow trout conducted in Oregon showed that the gene expression effects of aflatoxin B1 in rainbow trout strongly resemble those reported in human and rodent hepatocellular carcinoma. The published results validate that the trout model can be used to accurately evaluate cancer risk in humans and at a cost that is much less than conducting similar studies in rodents. Research conducted by the Michigan group showed that deoxynivalenol interfered with the immune response to reovirus infection. The subsequent publication demonstrated the likely mechanism of action and established the need for risk assessors to consider the occupational hazards associated with exposure to deoxynivalenol by farm workers. Oregon State and Berkeley are both conducting research activities to elucidate the effects of the indole-3-carbinol dimer (DIM) on tumor formation in various animal models. Oregon team members developed a trout gene chip and found that tumor promotion acted through an estrogenic pathway and continued after stopping DIM treatment, thus indicating no requirement for chronic exposure. The Berkeley group found that DIM has immune activating and antiangiogenic activity which reduced some tumors in other animal models. These results from emphasize the complex biological interactions which need to be considered with dietary supplements such as DIM. The Michigan group showed that the sensitivity of human white blood cells to the mycotoxin deoxynivalenol (DON or vomitoxin) was correlated with a specific protein kinase. Humans are 4-fold more sensitive to this kinase than are mice and DON sensitivity was found to vary among individuals, perhaps due to both genetic and non-genetic factors. The Michigan group found that deoxynivalenol (DON) induces a signaling cascade in the murine macrophage model (RAW 264.7 cells) that results in elevated TNF-alpha and MIP-2 gene expression. They also reported on studies showing that in peripheral mononuclear blood leukocytes, IL-6 and IL-8 were significantly induced by DON as was TNF-alpha. The group at Utah found that the age-related susceptibility of poultry to AFB1 may be due to the fact that microsomal AFB1 activation was most efficient in the youngest birds while the activity of hepatic cytosolic glutathione S-transferases were deficient in the youngest age group but higher in the older groups. The extreme sensitivity of young turkeys to the toxic effects of AFB1 may result from more efficient activation. The group at USDA-ARS Athens in collaboration with the group in Oregon found that dietary fumonisins are potent promoters of aflatoxin-initiated liver tumor formation in trout. This is important because aflatoxin and fumonisin co-occur in maize throughout the world. OBJECTIVE 3. Detect and identify new natural or induced bioactive compounds in foods that have beneficial or adverse effects on human health. 2006 A collaborative study by the group at Michigan and the group at Berkeley found that diindolylmethane (DIM) enhances immune response against reovirus gut infection. Overall, the results suggest that DIM enhanced both clearance of reovirus from the GI tract and the subsequent mucosal IgA response and have uncovered strong immune stimulating activities of DIM, which might contribute to the cancer inhibitory effects of this indole. This is an important observation that provides new insights into disease causation and prevention. The group at Berkeley found that DIM is a novel mitochondrial H+-ATP synthase inhibitor that can induce p21 expression by induction of oxidative stress in human breast cancer cells. These findings add additional support to the mechanistic understanding of this unique group of foodborne bioactive compounds. In a collaborative study with Korean scientists, the group at USDA-ARS Albany determined inhibitory effects of extracts of pigmented black rice brans on in vitro allergic reactions. The results suggest that polyphenol-rich pigmented rice brans merits further evaluation as part of a human diet to ascertain their potential to protect against allergic diseases such as hay fever and asthma. The group in Michigan found that trichothecene-mediated immunosuppression increased sensitivity of a host to enteric virus infection. Thus, in addition to systemic immune dysregulation trichothecenes also appear to interfere with mucosal host resistance. 2005 to 2002 Research was conducted by the group in Berkeley which showed that 3,3'-diindolymethane (DIM) could interfere with the signaling cascade necessary for angiogenesis. Publications documented the underlying mechanism provided medical researcher with a new mode of action for this intriguing dietary component. This work is important because it provides a new avenue of research that could lead to an improved understanding of tumor promotion. An improved HPLC method was developed by the USDA-ARS group in Albany and used to quantify potentially economically important chemicals in pepper fruit. This work was important because these improved methods will be used by the food industry to better evaluate food products and at lower cost to consumers. The USDA-ARS group in Athens developed an analytical method for detection of sphinganine-1-phophate in serum of animals exposed to subtoxic doses of fumonisins. Studies characterized a new sphingoid base metabolite in renal cells treated with fumonisin and suggested that this sphingoid could play an important role in fumonisin-induced renal toxicity. The group at Colorado found that curcumin, the yellow-coloring pigment in turmeric, inhibits biofilm formation and toxin production in Pseudomonas aeruginosa, which causes lung disease symptoms in cystic fibrosis. This was accomplished through inhibition of quorum sensing, a communication mechansim in the bacterium. Curcumin did not kill the bacteria, which remained alive, but were no longer capable of causing disease. The group at Colorado found that light and dark culture conditions and cell aggregate size, played an important role in growth of Hypericum perforatum L (St. Johns wort ) and production of its bioactive component, hypericin, in cell suspension cultures. A major gene termed Hyp-1 encoding for hypericin biosynthesis was cloned and characterized from H. perforatum L. cell cultures. In a separate study, the group at Colorado found that (-)-catechin, a root-secreted phytotoxin, contributes to Centaurea maculosas (spotted knapweed) invasive behavior in the rhizosphere. (+)-Catechin had antibacterial activity against root infesting pathogens while (-)-catechin did not. Results suggest that each enantiomer of racemic catechin contributes separate properties for plant aggression and defense. The W1122 researchers in Idaho identified several bioactive compounds in studies of wild and cultivated Vaccinium including blueberries, huckleberries, and cranberries. The wild Vaccinium species were highest in anthocyanin content. Of the aglycons studied, delphinidin and cyaniding were consistently found in the greatest amount while quercitin was typically found to be the most abundant of the flavonols. OBJECTIVE 4. Ascertain how agricultural production and food processing may influence production/stability of natural bioactive chemicals. 2006 The group at USDA-ARS Albany investigated the inhibition of Clostridium perfringens spore germination and outgrowth by the biopolymer chitosan during abusive chilling of cooked ground meat and turkey obtained from a retail store. The results suggest that incorporation of 3% chitosan into ground beef or turkey may reduce the potential risk of C. perfringens spore germination and outgrowth during abusive cooling. The USDA-ARS group in Athens evaluated the histological changes in rodent tissues following consumption of diets prepared by extrusion cooking from fumonisin-contaminated corn grits. It was found that extrusion cooking reduces in vivo toxicity if 10% glucose is added to the grits before extrusion and if the process reduces detectable fumonisin concentrations below a critical value. Extrusion without glucose supplementation had no beneficial effect. 2005 to 2002 Research was conducted by the USDA-ARS group in Athens in collaboration with food processors which showed that baking cookies and crackers did not appreciably destroy DON, but it was degraded or otherwise "lost" during the frying of donuts. These findings were provided to the USFDA and industry risk assessors to be used in the determination of the adequacy of current regulatory limits for deoxynivalenol. Maize samples analyzed the the USDA-ARS Athens group from highland (> 1700 m) areas in Guatemala were found to be far less contaminated with fumonisin and Fusarium verticillioides than lowland samples. This information is important because there is a concern that fumonisin exposure could contribute to neural tube defects in Guatemala, where NTD incidence is often very high. An exposure assessment was conducted and the findings were provided to risk managers in Guatemala to be used for the purposes of minimizing fumonisin exposure. The group at Davis conducted a survey of literature reports which attempted to compare the beneficial (detrimental) effects of organic vs. traditional agriculture in regard to human health. From a scientific viewpoint, few or none of the studies appeared to be conclusive and there was a significant lack of quantitative data. The Illinois group compared estrogenicity of minimally processed soy-based products consumed in Asian countries and more processed soys or pure isoflavones. The degree of soy flour processing affected the estrogenicity of products although all were compared to a constant level of the isoflavone genistein. Thus, refined products were more estrogenic than those which are minimally processed. The findings suggest that for postmenopausal women with estrogen-dependent breast cancer, the consumption of foods containing soy flour rather than refined products is more advisable. The USDA-ARS Athens group analyzed for fumonisins in maize grown in lowland and highland communities in Guatemala. Fumonisin often exceeded the maximal tolerable daily intake established by the WHO. Lowland corn, which is imported and used in the highlands, was found to be a source of greater fumonisin content than that grown locally in the highlands. The W1122 researches at California, Davis found that the fungicide metalaxyl appears to be a promising candidate for reducing fumonisin levels as cultures of Fusarium verticillioides grown in media containing the fungicide showed normal fungal growth but significantly reduced levels of fumonisins. The USDA-ARS Albany group conducted and published a comprehensive review of the chemical and biological basis of the formation in food and the toxicological effects of acrylamide. (WRRC) OBJECTIVE 5. Identify and investigate modes of action of food-borne factors which may reduce the impact of dietary carcinogens. 2006 The group in Illinois found that Genistein (GEN) can negate the aromatase inhibitory effects of letrozole (LET) on E-dependent tumor growth. It was concluded that dietary GEN increased the growth of implanted MCF-7Ca tumors in mice. Moreover, GEN negated the inhibitory effect of LET on MCF-7Ca tumor growth. These findings are significant because estrogen-dependent breast tumors, which express aromatase and can locally synthesize estrogens, are good candidates for successful aromatase therapy; however, the ability of dietary GEN to reverse the inhibitory effect of LET on tumor growth shows that this diet-drug interaction could adversely impact the course of breast cancer therapy. As previously shown for tamoxifen, caution is warranted for consumption of dietary GEN by postmenopausal women with estrogen-dependent breast cancer taking LET treatment. 2005 to 2002 Research was conducted by the group at Illinois to show that the soy chemical genestein acts in an additive manner with estrogen to stimulate growth of MCF-7 tumor growth in athymic mice. This finding is important because the safety of food products containing high levels of genestein is uncertain and establishing a level of exposure that is safe is a critically important issue in developed countries. The group in Illinois conducted a study to determine the ability of dietary genistein to negate or overwhelm the effectiveness of tamoxifen (TAM). In the presence of TAM estradiol implants, no growth of estrogen dependent tumor growth was observed. When genestein was present in the diet a significant increase in tumor growth was observed. Thus, genestein appears to negatively affect the efficacy of TAM; a widely used treatment for breast cancer. Other studies by the Illinois group found that diets containing soy flour can reduce the bioavailability of genestein or that there are other bioactive products in soy that can alter the effect of genestein. The group at Oregon showed that green and white teas effectively suppress tumor development in two mouse models of colorectal cancer. Both teas and molecular studies provide evidence that this is, at least in part, suppressing beta-catenin expression in normal intestinal mucosa.

Publications

ONLY PUBLICATIONS REPORTED AT THE 2006 MEETING ARE LISTED Allred, C. A., Allred, K.F., Ju, Y.H., Doerge, D.R., and Helferich, W.G. (2004) Soy processing influences growth of estrogen-dependent breast cancer tumors. Carcinogenesis 25(9):1649-1657 Allred, C.A., Allred, K.F., Ju, Y.H., Doerge, D.R., Schantz, S., Korol, D., and Helferich, W.G. (2004) Dietary genistein results in larger MNU-induced, estrogen-dependent mammary tumors following ovariectomy of Sprague-Dawley rats. Carcinogenesis 25:211-218. Allred, C.D., Twaddle, N.C., Allred, K.F., Churchwell, M.I., Ju, Y.H., Helferich, W.G., and Doerge, D.R. (200X) Soy processing affects metabolism and disposition of dietary isoflavones in ovariectomized Balb/c mice. J. Ag and Food Chem. (In Press) Brew, C.T., Aronchik, I., Hsu, J.C., Sheen, J.H., Dickson, R.B., Bjeldanes, L.F., Firestone, G.L. (2006) Indole-3-carbinol activates the ATM signaling pathway independent of DNA damage to stabilize p53 and induce G1 arrest of human mammary epithelial cells. Int. J. Cancer. 118(4):857-68. Chang, X., Firestone, G.L., Bjeldanes, L.F. (2006) Inhibition of growth factor-induced ras signaling in vascular endothelial cells and angiogenesis by 3,3'-diindolylmethane. Carcinogenesis. 27(3):541-50. Coulombe, R.A., Guarisco, J.A., Klein, P.J. and J.O. Hall (2005) Chemoprevention of aflatoxicosis in poultry by dietary butylated hydroxytoluene. Animal Feed Science and Technology 121: 217-225. Friedman, M. (2006) Nutritional evaluation of D-amino acids. In D-Amino Acids: A New Frontier in Amino Acid and Protein Research - Methods and Protocols, R. Kono and G. H. Fisher (Eds.), Nova Science Publishers, Happauge, New York, Chapter 4. Friedman, M., Buick, R., and Elliott, C. T. (2006) Antimicrobial activities of plant compounds against antibiotic-resistant Micrococcus luteus. Int. J. Antimicrob. Agents. 28: 156-158. Friedman, M., Henika, P. R., Levin, C. E., and Mandrell, R. W. (2006) Antimicrobial wine formulations against the foodborne pathogens Escherichia coli O157: H7 and Salmonella enterica. J. Food Sci. 71: M245-251. Friedman, M., Henika, P. R., Levin, C. E., Mandrell, R. E., and Kozukue, N. (2006) Antimicrobial activities of tea catechins and theaflavins and tea extracts against Bacillus cereus. J. Food Prot. 69: 354-361. Friedman, M., Levin, C. E., Choi, S.-H., Kozukue, E., and Kozukue, N. (2006) HPLC analysis of catechins, theaflavins, and alkaloids in commercial teas and green tea dietary supplements: comparison of water and 80% ethanol/water extracts. J. Food Sci. 71: C328-C337. Gong Y, Firestone, G.L., Bjeldanes,L.F. (2006) 3,3'-Diindolylmethane (DIM) is a novel topoisomerase II{alpha} catalytic inhibitor that induces S phase retardation and mitotic delay in human hepatoma HepG2 cells. Mol Pharmacol. Mol. Pharmacol. 69(4):1320-7. Gong, Y., Sohn, H., Xue, L,. Firestone, G.L., Bjeldanes, L.F. (2006) 3,3'-Diindolylmethane is a novel mitochondrial H(+)-ATP synthase inhibitor that can induce p21(Cip1/Waf1) expression by induction of oxidative stress in human breast cancer cells. Cancer Res. 66(9):4880-7. Hsu JC, Dev A, Wing A, Brew CT, Bjeldanes LF, Firestone GL. (2006) Indole-3-carbinol mediated cell cycle arrest of LNCaP human prostate cancer cells requires the induced production of activated p53 tumor suppressor protein. Biochem Pharmacol. 2006 Sep 11; [Epub ahead of print]. Hsu, J.C., Zhang, J., Dev, A., Wing, A., Bjeldanes, L.F,. Firestone, G.L. (2005) Indole-3-carbinol inhibition of androgen receptor expression and down-regulation of androgen responsiveness in human prostate cancer cells. Carcinogenesis. 26(11): 1896-904. Islam, Z., and Pestka, J. J. (2006). LPS priming potentiates and prolongs proinflammatory cytokine response to the trichothecene deoxynivalenol in the mouse. Toxicol. Appl. Pharmacol. 211(1), 53-63. Islam, Z., Gray, J. S., and Pestka, J. J. (2006). p38 Mitogen-activated protein kinase mediates IL-8 induction by the ribotoxin deoxynivalenol in human monocytes. Toxicol. Appl. Pharmacol. 213(3), 235-244. Islam, Z., Harkema, J. R., and Pestka, J. J. (2006). Satratoxin G from the black mold Stachybotrys chartarum evokes olfactory sensory neuron loss and inflammation in the murine nose and brain. Environ. Health Perspect. 114(7), 1099-1107. Jia, Q., and Pestka, J. J. (2005). Role of cyclooxygenase-2 in deoxynivalenol-induced immunoglobulin a nephropathy. Food Chem. Toxicol. 43(5), 721-728. Jia, Q., Zhou, H. R., Shi, Y., and Pestka, J. J. (2006). Docosahexaenoic acid consumption inhibits deoxynivalenol-induced CREB/ATF1 activation and IL-6 gene transcription in mouse macrophages. J. Nutr. 136(2), 366-372. Ju, Y. H., Allred K.F., Allred, C.D., and Helferich, W.G. (200X) The Soy Isoflavone, Genistein, Stimulates the Growth of Human Breast Cancer Cells In Vivo in the Presence of Low Plasma Levels of Estradiol. (Submitted) Carcinogenesis Ju, Y. H., Fultz J, Allred K.F., Doerge D.R., and Helferich, W.G. (200X) Effects Of Dietary Daidzein And Its Metabolite, Equol, At Physiological Concentrations On The Growth Of Estrogen-Dependent Human Breast Cancer (MCF-7) Tumor Implanted In Ovariectomized Athymic Mice. (In Press) Carcinogenesis Ju, Y.H., Clausen, L.M., Almada, A.L., and Helferich, W.G. (2004) Beta$-sitosterol, $Beta-sitosterol glucoside, and a mixture of $Beta- sitosterol and $-sitosterol glucoside modulate the growth of estrogen-responsive breast cancer cells in vitro and in ovariectomized athymic mice. J. Nutr. (In Press) Jubert, C and Bailey, G. (200x). Large-Scale Isolation of Chlorophyll a and b from Spinach by Counter-Current Chromatography. Journal of Chromatography A, (submitted). Juneja, V. K., Thippareddi, H., and Friedman, M. (2006) Control of Clostridium perfringens in cooked ground beef by carvacrol, cinnamaldehyde, thymol, or oregano oil during chilling. J. Food Prot. 69: 1546-1551. Juneja, V. K., Thippareddi, H., Bari, L., Inatsu, Y., Kawamoto, S., and Friedman, M. (2006) Chitosan protects cooked ground beef and turkey against Clostridium perfringens spores during chilling. J. Food Sci. 71: M236-M240. Kinser, S., Li, M., Jia, Q., and Pestka, J. J. (2005). Truncated deoxynivalenol-induced splenic immediate early gene response in mice consuming (n-3) polyunsaturated fatty acids. J. Nutr. Biochem. 16(2), 88-95. Kozukue, N., Han, J. S., Kozukue, E., Lee, S. J., Kim, J. A., Lee, K. R., Levin, C. E., and Friedman, M. (2005) Analysis of eight capsaicinoids in peppers and pepper-containing foods by high-performance liquid chromatography and liquid chromatography-mass spectrometry. J. Agric. Food Chem. 53: 9172-9181. Kwon, D., Yoon, S., Carter, O., Bailey, G.S., Dashwood, R.H. (200x) Antioxidant and antigenotoxic activities of Angelica keiskei, Oenanthe javanica and Brassica oleracea in the Salmonella mutagenicity assay and in HCT116 human colon cancer cells. BioFactors, in press Li, M., Cuff, C. F., and Pestka, J. (2005). Modulation of murine host response to enteric reovirus infection by the trichothecene deoxynivalenol. Toxicol. Sci. 87(1), 134-145. Li, M., Cuff, C. F., and Pestka, J. J. (2006). T-2 toxin impairment of enteric reovirus clearance in the mouse associated with suppressed immunoglobulin and IFN-gamma responses. Toxicol. Appl. Pharmacol. 214(3), 318-325. Li, M., Harkema, J. R., Islam, Z., Cuff, C. F., and Pestka, J. J. (2006). T-2 toxin impairs murine immune response to respiratory reovirus and exacerbates viral bronchiolitis. Toxicol. Appl. Pharmacol. (in press) Mbandi, E., and Pestka, J. J. (2006). Deoxynivalenol and satratoxin G potentiate proinflammatory cytokine and macrophage inhibitory protein 2 induction by Listeria and Salmonella in the macrophage. J. Food Prot. 69(6), 1334-1339. Muthyala, R.S., Ju, Y.H., Sheng, S., Williams, L.D., Doerge, D.R., Katzenellenbogen, B.S., Helferich, W.G., and Katzenellenbogen, J.A. (2004) Equol, a natural estrogenic metabolite from soy isoflavones: convenient synthesis and resolution of R- and S-equol and their biological activity through the estrogen receptors alpha and beta. Bioorganic & Medicinal Chemistry 12(6): 1559-567. Nam, S. H., Choi, S. P., Kang, M. Y., Koh, H. J., Kozukue, N., and Friedman, M. (2006) Antioxidative activities of bran extracts from twenty one pigmented rice cultivars. Food Chem. 94: 613-620. Orner GA., Roebuck BD., Dashwood RH., Bailey GS. 2006. Post-initiation chlorophyllin exposure does not modulate aflatoxin-induced foci in the liver and colon of rats. Journal of Carcinogenesis 2006, 5:6. Pestka, J. J., and Smolinski, A. T. (2005). Deoxynivalenol: toxicology and potential effects on humans. J. Toxicol. Environ. Health B Crit Rev. 8(1), 39-69. Pestka, J. J., Uzarski, R. L., and Islam, Z. (2005). Induction of apoptosis and cytokine production in the Jurkat human T cells by deoxynivalenol: role of mitogen-activated protein kinases and comparison to other 8-ketotrichothecenes. Toxicology 206 (2), 207-219 Pestka, J., and Zhou, H. R. (2006). Toll-like receptor priming sensitizes macrophages to proinflammatory cytokine gene induction by deoxynivalenol and other toxicants. Toxicol. Sci. 92(2), 445-455. Pratt, M. M., Reddy, A. P., Hendricks, J.D., Pereira, C., Kensler, T.W., and Bailey, G.S. (2006). The importance of carcinogen dose in chemoprevention studies: quantitative interrelationships between, dibenzo[a,l]pyrene dose, chlorophyllin dose, target organ DNA adduct biomarkers, and final tumor outcome. Carcinogenesis doi: 10.1093/carcin/bgl174 Reed, K.M., Mendoza, K.M. and R. A. Coulombe, Jr. (2006). Structure and genetic mapping of the Cytochrome P4501A5 gene in the turkey (Meleagris gallopavo). Cytogenetics and Genome Research (in press). Riby, J.E., Xue, L., Chatterji, U., Bjeldanes, E.L., Firestone, G.L., Bjeldanes, L.F. (2006) Activation and potentiation of interferon-g signaling by 3,3-diindolylmethane in MCF-7 breast cancer cells. Mol. Pharmacol. 69(2):430-9. Riley RT, Voss KA, Speer M, Stevens VL, Gelineau-van Waes J. (2006) Fumonisin inhibition of ceramide synthase: A possible risk factor for human neural tube defects. In, Y. Hirabayashi , A. Merrill, and Y. Igarashi (Eds) Sphingolipid Biology, pp. 345-362, Springer Verlag, Tokyo. Riley RT, Voss KA. (2006) Differential sensitivity of rat kidney and liver to fumonisin toxicity: Organ specific differences in toxin accumulation and sphingoid base metabolism. Toxicological Science 92: 335-345. Riley, R.T., Torres, O.A., Palencia, E. (2006) International shipping of fumonisins from maize extracts on C18 sorbent. Food Additives and Contaminants. 23: 826-832. Selvaraj V, Zakroczymski MA, Naaz A, Mukai M, Ju YH, Doerge DR, Katzenellenbogen JA, Helferich WG, Cooke PS (2004) Estrogenicity of the isoflavone metabolite equol on reproductive and non-reproductive organs in mice. Biology of Reproduction 71:966-972. Sharma, R.P., He, Q. and Riley, R.T. (2005) Lupus-prone NZBWF1/J mice, defective in cytokine signaling, are resistant to fumonisin hepatotoxicity despite accumulation of liver sphinganine. Toxicology 216: 59-71. Shi, Y., and Pestka, J. J. (2006). Attenuation of mycotoxin-induced IgA nephropathy by eicosapentaenoic acid in the mouse: dose response and relation to IL-6 expression. J. Nutr. Biochem. 17(10), 697-706. Simonich, M.T., Egner, P.E., Roebuck, B.D., Orner, G., Jubert, C., Pereira, C., Groopman, J.D., Kensler, T.W., Dashwood, R.H., Williams, D., and Bailey, G.S. (200x). Natural chlorophyll inhibits aflatoxin B1 induced multi-organ carcinogenesis in the rat. Carcinogenesis, (submitted) Simonich, M.T., McQuistan, T., Jubert, C., Pereira, C., Hendricks, J.D., Dashwood, R.H., Williams, D., and Bailey, G.S. (200x). Natural chlorophyll inhibits dibenzo[a,l]pyrene-induced multi-organ carcinogenesis in the rainbow trout. Carcinogenesis, (submitted). Smolinski, A. T., and Pestka, J. J. (2005). Comparative effects of the herbal constituent parthenolide (Feverfew) on lipopolysaccharide-induced inflammatory gene expression in murine spleen and liver. J. Inflamm. (Lond) 2, 6. Staub, R.E., Onisko, B., Bjeldanes, L.F. (2006) Fate of 3,3'-diindolylmethane in cultured mcf-7 human breast cancer cells. Chem Res Toxicol. 19(3):436-42, Sundar SN, Kerekatte V, Equinozio CN, Doan VB, Bjeldanes LF, Firestone GL. (2006) Indole-3-Carbinol (I3C) selectively uncouples expression and activity of estrogen receptor subtypes in human breast cancer cells. Mol Endocrinol. 2006 Aug 10; [Epub ahead of print]. Tilton, S.C., Hendricks, J.D., Orner, G.A., Pereira, C.B., Bailey, G.S., and Williams, D.E. (200x) Gene expression analysis during tumor enhancement by the dietary phytochemical, 3,3-diindolylmethane, in rainbow trout. (Submitted) Urraca, J. L., ito-Pena, E., Perez-Conde, C., Moreno-Bondi, M. C., and Pestka, J. J. (2005). Analysis of zearalenone in cereal and Swine feed samples using an automated flow-through immunosensor. J. Agric. Food Chem. 53(9), 3338-3344. Van Vleet, T.R., Watterson, T.L., Klein, P.J., and R.A. Coulombe, Jr. (2006). Aflatoxin B1 alters the expression of p53 in cytochrome P450-expressing human lung cells. Toxicological Sciences. 89, 399-407. Vivanti, V., Finotti, E., and Friedman, M. (2006) Level of acrylamide precursors asparagine, fructose, glucose, and sucrose in potatoes sold at retail in Italy and in the United States. J. Food Sci. 71: C81-C85. Voss KA Gelineau-van Waes, Riley RT. (2006) Fumonisins: current research trends in developmental toxicology. Mycotoxin Research 22, 61-69. Voss KA, Liu J, Anderson SP, Dunn C, Miller JD, Owen JR, Riley RT, Bacon CW, Corton JC. (2006)Toxic effects of fumonisin in mouse liver are independent of the peroxisome proliferator-activated receptor ±. Toxicological Science 89:108-119. Voss KA, Norred WP, Meredith FI, Riley RT, Saunders DS. (2006) Fumonisin concentration and ceramide synthase inhibitory activity of corn, masa and tortilla chips. Journal of Toxicology and Environmental Health (Part A) 69:1387-1397. Voss KA, Riley RT, Dunn C, Corton JC. (2006) The role of tumor necrosis factor a and the peroxisome proliferator-activated receptor a in modulating the effects of fumonisin in mouse liver. Toxicology 222:165-174. Voss KA, Riley RT, Gelineau van-Waes JB. (2005) Trends in fumonisin research: recent studies on the developmental effects of fumonisins and Fusarium verticillioides. Mycotoxins (Japan), 55:91-100. Wang, R., Dashwood, W.M., Bailey, G.S., Williams, D.E., and Dashwood, R.H. (2006) Tumors from rats given 1,2-dimethylhydrazine plus chlorophyllin or indole-3-carbinol contain transcriptional changes in b-catenin that are independent of b-catenin mutation status. Mutation Res. (in press) Watterson, T.L., Sorenson, J., Martin, R., and R.A. Coulombe, Jr. (200X). Effects of PM2.5 Collected from Cache Valley Utah on Genes Associated with the Inflammatory Response in Human Lung Cells. Toxicology and Applied Pharmacology. (submitted). Williams, L.D., Glenn, A.E., Bacon, C.W., Smith, M.A.and Riley, R.T. (2006) Fumonisin production and bioavailability to maize seedlings grown from seeds inoculated with Fusarium verticillioides and grown in natural soils. Journal of Agricultural and Food Chemistry. 54: 5694-5700. Xiao S, Anderson SP, Swanson C, Bahnemann R, Voss KA, Stauber AJ, Corten JC. (2006) Activation of peroxisome proliferator activated receptor ± (PPAR ±) enhances apoptosis in mouse liver. Toxicological Science 92: 368-377. Xue L, Li M, Pestka JJ, Firestone GL, Bjeldanes LF. (200X) 3,3-Diindolylmethane is a novel immunomodulator that activates cytokine production, lymphocyte proliferation, and reovirus clearance. J Nutrition [submitted] Yip, S.S.M. and R.A. Coulombe, Jr. (2006) Molecular cloning and expression of a novel cytochrome P450 from turkey liver with aflatoxin B1 metabolizing activity. Chemical Research in Toxicology 19:30-37. Yu, Z., Loehr, C., Fischer, K., Louderback, M., Kreuger, S., Dashwood, R., Kerkvliet, N., Pereira, C., Jennings-Jee, J., Dance, S., Miller, M., Bailey, G. and Williams, D. (2006). In utero exposure of mice to dibenzo(a,l)pyrene produces lymphomas in the offspring: Role of the aryl hydrocarbon receptor. Cancer Res. 66:755-762. Zhou, H. R., Islam, Z., and Pestka, J. J. (2005). Induction of competing apoptotic and survival signaling pathways in the macrophage by the ribotoxic trichothecene deoxynivalenol. Toxicol. Sci. 87(1), 113-122. Zhou, H. R., Jia, Q., and Pestka, J. J. (2005). Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. Toxicol. Sci. 85(2), 916-926.

Impact Statements

SUMMARY IMPACT. Over the 5 year span of this project the W1122 activities have greatly increased the understanding of the molecular mechanisms underlying the impact of dietary chemicals on health. This information has been applied to real-world problems in clinical trials, and intervention studies and has been used by authoritative bodies in formulating regulatory guidelines for industry and for protecting and improving the health of consumers. A selection of impacts are briefly summarized below as evidence of the W1122 payoff to society.
Reduced cancer incidence in countries where exposure to aflatoxins and other DNA reactive carcinogens are high. W-1122 participants have shown that chlorophyll and its derivatives can function as anticarcinogens and block the action of food-borne genotoxic chemicals such as aflatoxin and heterocyclic amines. Risk of liver, colon, stomach, breast, prostate, and lung cancer, which include the leading causes of cancer death in the US and the world, may be significantly reduced by appropriate daily intake of simple, safe, inexpensive chlorophyll derivatives.
Improved consumer health and decreased human morbidity and mortality. Indole-3-carbinol and 3,3-diindolylmethane (DIM) are two potential chemopreventive agents from Brassica. Mechanistic studies have revealed several functions and novel mechanisms of action relevant to multi-organ cancer prevention and therapy, immune enhancement, potentiation of gastric clearance of reovirus and inhibition of tumor angiogenesis. Taken together, these studies have identified several complementary effects and modes of action of DIM that are being exploited in the development of this natural substance as a cancer chemopreventive or therapeutic agent.
Decreased risk of birth defects. W-1122 researchers completed a five year collaborative study that measured the levels of fumonisins in maize grown in the highlands and lowlands of Guatemala. The data were used to develop an exposure assessment for women in Guatemala. Based on the exposure assessment, recommendations for minimizing fumonisin exposure were provided to the Consejo Nacional de Ciencia y Tecnologia in September of 2005. A consumer education program has been proposed in Guatemala for the purpose of ensuring that consumers are aware of steps in traditional processing that should be taken to improve the safety of maize products.
Increased consumer confidence.W1122 researchers have determined that the principal mode for tumor enhancement by indoles in animals lies in their potential for estrogenic effects in the liver. Exploration of such effects in humans will be essential for establishing human risk, if any, and for identifying individuals most likely to benefit from indole intervention. Understanding the mechanistic basis for DIM biological activity is a key component of the risk analysis and the information provided by W1122 researchers reduces the uncertainty in the risk assessment and thus improves consumer confidence.
Improved risk analysis. W1122 research activities showed that the soy chemical genestein acts in an additive manner with estrogen to stimulate growth of MCF-7 tumor growth in mice and reversed the effect of aromatase inhibitors used to treat estrogen-dependent breast tumors. Establishing a level of exposure that is safe is a critically important issue for consumers and the medical community since caution is warranted for consumption of dietary genestein by postmenopausal women with estrogen-dependent breast cancer that are taking aromatase inhibitor therapy.
Improved risk analysis.Research activities on mechanism of action conducted by the W1122 participants in Georgia, Michigan, Oregon and Utah have served to strengthen the ongoing mycotoxin risk assessment for aflatoxins, trichothecenes and fumonisins. These studies serve to reduce the uncertainty and allow for setting of maximum limits and tolerable daily intakes that prevent over regulation of important US exports including wheat and corn. Information was used by the WHO/FAO Joint Expert Committee on Food Additives, International Agency for Research Cancer, and ILSI Europe.
Increased profits for industry.W1122 research activity has identified numerous novel compounds that have efficacy in disease prevention and have the potential of increasing agricultural profitability. W1122 research has developed methods of analysis and tested numerous new types of effective and non-toxic antimicrobial plant-derived compounds potentially useful against foodborne pathogens including Escherichia coli O157:H7, Listeria monocytogenes, Salmonella enterica, Bacillus cereus, and Clostridium perfringens.
Reduced economic losses for industry.Research activities by the group at Utah State University found that dietary butylated hydroxytoluene (BHT) protects against clinical signs of aflatoxicosis in turkeys, with concentrations as low as 100 ppm BHT providing protection against some signs of aflatoxicosis. Finding chemoprevention strategies in domestic food animals such as poultry will help American agriculture produce a safer product for consumers. This research was featured in the magazine Science Digest in March 2005
Reduced cost and increased sensitivity of testing.W-1122 researchers have pioneered rainbow trout as a model to establish risk of dietary carcinogens and to identify potential chemopreventives. The model solves the logistical difficulty inherent in using rodents for testing. A recent 42,000 trout ultra-low dose tumor study utilizing dibenzo[a,l]pyrene (DBP) established the dose-response to 1 additional cancer in 5,000 animals. A significant negative departure from the EPA conservative linear model was observed. The implications of these findings in risk assessment are profound.
Reduced health care cost and improved health. Immunonutrition is an emerging emphasis area in food safety research. W-1122 researchers identified natural immune system modulators that can potentially protect against a range of disease processes from viral infection to cancer. For example, Omega-3 fatty acid consumption by mice causes macrophages of the innate immune system to be reprogrammed. As a result, induction of inflammatory gene expression by toxins and stress is suppressed thereby leading to decreased disease.