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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>Selected classes of bioactive compounds show potential for beneficial or adverse effects on human health. We will discover bioactive compounds that have beneficial or adverse effects on human health.
NON-TECHNICAL SUMMARY: Issues related to food safety and to diet and health impact many, including consumers, agricultural producers, food processors, health professional and policy makers charged with maintaining a safe and nutritious food supply. The proposed work, to be integrated and carried out in collaboration with other investigators in this ongoing project, is focused on the identification and characterization of natural and synthetic chemicals present in food that affect hormone receptors and the impact of these interactions on normal endocrine function in humans and animals. The identification and characterization of dietary bioactive chemicals that affect these signaling pathways and cell proliferation will permit development of novel human therapeutic drugs that can be tested in collaboration with investigators in the W2122 project.
<P>APPROACH: Humans and animals are chronically exposed to a diverse array of natural, bioactive chemicals present in our food. While the ability of these substances to produce adverse human health effects has been well established, other naturally occurring chemicals can improve human health and reduce the onset/progress of human diseases such as cancer. Identification and characterization of these toxic and beneficial natural products and elucidation of their molecular mechanisms will provide insights into the acceptable levels of these chemicals in foods, and may lead to the development of "designer" foods and/or food-derived products for use in the prevention and modulation of human disease. Newly identified bioactive natural products could lead to the development of human therapeutic drugs. We propose to contribute to three of the currently defined objectives in the W2122 program. In objective 1, we will examine the molecular mechanisms by which natural dietary chemicals (flavonoids, indirubins, polyphenolics and others) can interact with and activate/inhibit the functionality of ligand-dependent nuclear transcription factors, such as steroid hormone and related nuclear receptors and the aryl hydrocarbon receptor. These receptors play key regulatory roles in cancer and inflammatory processes. In addition, the ability of these products to inhibit growth and proliferation of human and animal cancer cell lines and the role of these nuclear receptors in mediating this inhibition will be determined by examining their impact on cell cycle and cell proliferative signaling pathways. In objective 2, human and rodent cell lines will be used to examine the molecular mechanisms by which naturally occurring chemicals and food-borne toxicants can produce or enhance toxicity (i.e., endocrine disruption) mediated by nuclear receptors. In these experiments we will examine the ability of these test chemicals and extracts to alter the functional activity of hormone/Ah receptor signaling pathways in recombinant human cells in culture. We will subsequently use a variety of biochemical and molecular approaches to determine the specific step(s) in the target receptor-dependent mechanism of action that is affected by the test compound(s) and determine if the chemical exerts its effect directly on the receptor or in an indirect manner. Finally, in objective 3, recombinant cell lines will be used to screen extracts of food and herbal products to identify those containing natural products that can modulate the functionality of these receptors and to permit isolation of the responsible bioactive chemicals. These studies will utilize recombinant cell lines that contain stably transfected receptor-responsive reporter genes that we have demonstrated to work efficiently as bioassay systems for the identification of novel chemicals that exhibit receptor agonist and/or antagonist activity. The relative potency, efficacy and persistence of each chemical/extract on the identified receptor will be determined and compared to its high affinity ligand (steroid or dioxin).