Endocrine Disruptors: Assessment of endocrine disruption activity, mechanism and

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DESCRIPTION (provided by applicant): Cancer is a major cause of death in United States and around the world. Numerous studies suggest that in addition to genetic factors, environmental factors, food habit and geographic location have significant contribution to the rate of cancer incidence. Among the environmental factors Endocrine Disrupting Chemicals (EDCs) appear to be a major contributor towards several human diseases including cancer. EDCs are family of chemicals that mimic hormones and interfere with normal hormonal functions resulting in adverse effects on human and animal health. Sources of EDCs may include daily foods, drinking water, plastics, pesticides, synthetic hormones etc. Although EDCs are major health concern, knowledge is still limited in terms of their endocrine disruption activity, mechanism of action and health risk. Based on our expertise on estrogen signaling, gene regulation and epigenetics biochemistry, we proposed to a) asses the endocrine disruption activity of various known and unknown EDCs, b) understand their mechanism of action and c) outreach to the community to increase the awareness about EDCs. In order to develop assays for the analysis of EDC activity, we propose to utilize the promoter of estrogen responsive HOX genes that are key players in embryonic development. Recently, we found that estrogen (E2) transcriptionally regulates several HOX genes including HOXC13 and paralogous genes (HOXA13, B13 and D13). HOXC13 promoter contains multiple estrogen response elements (EREs) to which estrogen receptors (ER: ERa and ER¿) bind during E2-mediated gene activation. Importantly, we also found that mixed lineage leukemia (MLL) family of histone methyl-transferases that are crucial players in gene activation, interact with ERs and bind to these EREs to regulate HOXC13 expression in presence of E2. Based on these findings, we hypothesize that HOXC13 and paralogous genes are regulated by ERs and MLLs (as coregulators). Herein, we propose to investigate the epigenetic regulatory mechanisms of E2-mediated transcriptional regulation of HOXC13 and paralogous genes and expand this knowledge to develop novel cell based assays to assess the endocrine disruption activity of various known and unknown EDCs and understand their mechanisms of action. In addition, we also propose to outreach to the community (through service learning) to increase awareness about EDCs. These studies will unfold the epigenetic regulatory mechanism of E2- mediated regulation of HOX genes. In addition, these studies will provide novel insights about the action of EDCs and also provide novel assays to assess the endocrine disruption activities of various known and unknown EDCs. The outreach activity will increase the local community awareness about EDCs and their relevance to human health and society that will have high impact on quality of human health, and may reduce the incidence of cancer and other diseases. PUBLIC HEALTH RELEVANCE: Endocrine Disrupting Chemicals (EDCs) are family of chemicals that mimic hormones and interfere with normal hormonal functions resulting in adverse effects on reproduction, behavior and development ultimately causing severe human diseases including cancer. Herein, experiments are proposed to a) asses the endocrine disruption activity of various known and unknown EDCs, b) understand their mechanism of action and c) outreach to the community to increase the awareness about EDCs. These studies will have high impact on quality of human life, health and may reduce the incidence of cancer and other diseases in long run.