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

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 W1122 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 W1122 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).<P>
PROGRESS: 2002/10 TO 2007/09<BR>
Discussions I had with existing members of the W1122 project regarding my ongoing research on natural and dietary chemicals and their beneficial and adverse health effects, I was invited to participate in the annual national meeting in Monterey, California in the fall of 2006. I presented an overview of our method, approaches and studies on the identification and characterization of natural and synthetic chemicals present in food and their effects on normal endocrine hormone function in humans and animals. Based on our work, ongoing collaborations we already had with two members of the program (Dr. William Helferich and Dr. Leonard Bjeldanes) and obvious collaborative potentials we had with several other members of the program, I was invited and to join the program as soon as possible and participate in the writing of the competitive renewal that was being prepared for submission in the spring of 2007. Accordingly, while I was added to the project, I was not added to the CA project until March 2007, too late to receive any CSREES funds for project year period of 10/1/06-9/30/07. Thus, we were unable to do any significant work on the project. However, the 5-year competitive renewal was funded and I am an active participate on the new project that started on 10/1/07. The work we have proposed in the upcoming 5-year period will be integrated and carried out in collaboration with other investigators in this ongoing project. Our studies are 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. We have already established and validated several animal and human cell- and in vitro-based bioassay systems and confirmed their ability to respond to model chemicals and these systems will be used to identify and isolate natural and synthetic bioactive chemicals present in food and to characterize their beneficial and adverse effects. A major goal is the identification and characterization of selective dietary bioactive chemicals that affect these signaling pathways and lead to the inhibition of human cancer cell proliferation. These studies will be the first step in the development novel human therapeutic and chemotherapeutic drugs from naturally-occurring chemicals present in food and their functional activity tested in vitro and in vivo in collaboration with investigators in the W1122 project. <P>IMPACT: 2002/10 TO 2007/09<BR>
There are no outcomes to report at the present time as I joined the project in the middle of its final year and as such, it was too late to receive any CSREES funds to support work on this project.