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To understand the health effects of environmental chemicals as a function of their ability to act as ligands for certain ligand-activated transcription factors (TFs). Ultimately, we will understand the changes in gene expression that result from TF activation that lead to toxicity. <P>Over the program period, we plan: (1) To identify biomarkers that are expressed in response to a set of relevant model toxicants, to generate stable reporter animals using gene regulatory elements (Tanguay); (2) To assess the risk of dioxins to humans and understand the downstream pathways and novel antagonists for mediating toxicity (Kolluri); (3) To investigate the underlying mechanisms of immune suppression. (Kerkvliet); and (4) Through the modulation of the maternal diet, reduce the risk of the fetus to toxic chemicals capable of crossing the placenta (Williams).
Non-Technical Summary: It is becoming increasingly apparent that the overall approach to toxicity testing of chemicals found in the human environment is not meeting the needs of society. With current testing paradigms, we spend most of our energy testing a limited number of chemicals in extensive testing protocols using laboratory animals; however, the vast majority of chemicals that are present in the environment as a consequence of their manufacture, use, or intentional consumption have not been tested for their toxicity. Thus there is a need for a new strategy for testing xenobiotics that will lead to the early identification of hazardous chemicals, as well as to an understanding of the mechanism(s) by which a given chemical causes toxic and other health related effects. The research will utilize several model systems and several disease endpoints to understand the changes cell signaling induced in different target tissues by chemicals. Results of this research will contribute to the development and validation of new models for toxicity testing, to the identification of underlying molecular mechanisms of toxicant action, and to the ability of other chemicals to prevent or mitigate the toxic effects of environmental chemicals. <P> Approach: The research will focus on studying chemicals that bind and activate transcription factors (TFs), specialized DNA-binding proteins that bind to promoter regions of specific genes and regulate gene transcription. The research will utilize several model systems and several disease endpoints to understand the changes cell signaling induced in different target tissues by chemicals. In addition, exposure to other chemicals that are found in the food supply or consumed as nutritional supplements have to potential to counteract this toxicity, through several possible mechanisms. This TFC group has expertise in several model systems with different health endpoints under investigation. Understanding how environmental chemicals hijack the normal transcriptional machinery will play a major role in determining the risk to human health from exposure as well as treatment regimes that could alleviate toxicity if exposure occurs. Expertise using the zebrafish model will contribute to the validation of the zebrafish as a screening tool for toxicity testing and for elucidating mechanisms of toxicant action. Results of this research will contribute to the development and validation of new models for toxicity testing, to the identification of underlying molecular mechanisms of toxicant action, and to the ability of other chemicals to prevent or mitigate the toxic effects of environmental chemicals. IBC and IACUC approvals will be obtained as experiments are defined.