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<OL> <LI>Consumption of food-borne bioactive compounds can protect against human diseases such as cancer, inflammation, birth defects, and microbial infection. We will determine the mechanisms by which selected compounds exert their protective action. <LI> Food-borne toxins and carcinogens are present per se or are induced by processing, preparation, and other post-harvest steps. We will identify mechanisms of action and develop biomarkers of natural and induced toxicants in food for human risk assessment and disease prevention. <LI> Modifying foods is an increasingly important strategy to improve nutrition and safety. Therefore, we will improve food safety by developing approaches to increase beneficial or decrease adverse effects of bioactive food constituents and microbial contaminants.
Non-Technical Summary: Foods contain naturally-occurring substances that are beneficial, as well as some that have an adverse effect on human health. The purpose of this project is to improve public health by identifying and determining the mechanism of action of those substances. This is the first demonstration that dietary antioxidants actually reduce the residual concentrations of a naturally-occurring food-borne carcinogen aflatoxin B1 (AFB1) in turkeys. Because AFB1 is a known human carcinogen, this research will help improve the safety of our food supply by reducing human exposure to natural cancer-causing chemicals. <P> Approach: 1. Antioxidants have been shown to reduce bioavailability, increase excretion, and reduce residues of AFB1 in turkey meat products, and therefore is a potential strategy to improve food safety. We will assess the potential chemoprotective properties of antioxidants against aflatoxin B1 (AFB1)-induced toxicity in poultry as well as on residues of mycotoxins such as AFB1 in commercially-important tissues, such as breast meat and fat. Determination of residual antioxidants will also be determined to insure that the levels fall within acceptable limits set by the US FDA. Phase I and phase II enzymes important in AFB1 bioactivation and detoxification, such as cytochromes P450 (CYP) and glutathione S-transferase (GST), will be characterized for their role cancer susceptibility and resistance. 2. The cytochrome P450 1A5 gene (CYP1A5) which we recently cloned from turkey liver has high activity toward AFB1 bioactivation. This gene bears substantial homology to human CYP1A2 which bioactivates many dietary carcinogens, such as AFB1. Thus, the turkey homologue can be considered as a model for a human CYP gene associated with cancer risk, and studies here can provide information on the molecular basis of cancer susceptibility in people. This gene will be mapped with the goal of establishing molecular determinants in conserved motifs that underlie hypersusceptibility toward this potent hepatocarcinogen. In addition, the molecular mechanism of regulation of expression of CYP1A5 and the implications on AFB1 bioactivation will be carried out in collaboration with W-2112 colleagues. 3. We will explore strategies to transform plants with enzymes to detoxify dietary carcinogens, like AFB1. We will use cDNA from cloned CYP genes, such as CYP2K1 from rainbow trout, which converts AFB1 to an unstable epoxide that should readily react with abundant plant nucleophiles. Plants thus transformed would convert AFB1 contamination into safe endproducts. Production of plants, such as maize, transformed with genes coding for increased AFB1 detoxification pathways represents a potentially valuable pre-harvest AFB1 elimination strategy that would result in a safer food for animals and people. 4. Using a poultry model for AFB1 hypersensitivity, we will test the effectiveness of chemopreventives shown in mammalian studies to protect against the toxic and carcinogenic activities of mycotoxins such as AFB1. These include antioxidants shown to inhibit CYP-dependent AFB1 bioactivation, such as ethoxyquin, and agents shown to prevent absorption of AFB1 such as probiotic Lactobacillus rhamnosus. For those compounds that are shown to be protective, molecular mechanisms of protection will be explored.