Endocrine Disruptors: Assessment of endocrine disruption activity, mechanism and

描述（由申请人提供）：癌症是美国和世界各地的主要死因。大量研究表明，除了遗传因素外，环境因素、饮食习惯和地理位置对癌症发病率有重要影响。在环境因素中，内分泌干扰化学品（EDCs）似乎是导致包括癌症在内的几种人类疾病的主要因素。内分泌干扰物是一系列化学物质，它们模拟激素并干扰正常的激素功能，对人类和动物健康产生不利影响。内分泌干扰物的来源可能包括日常食物、饮用水、塑料、杀虫剂、合成激素等。虽然内分泌干扰物是主要的健康问题，但就其内分泌干扰活性、作用机制和健康风险而言，知识仍然有限。基于我们在雌激素信号传导、基因调控和表观遗传学生物化学方面的专业知识，我们建议a）评估各种已知和未知的内分泌干扰物的内分泌干扰活性，B）了解其作用机制，以及c）向社区推广以提高对内分泌干扰物的认识。为了开发用于分析EDC活性的测定法，我们建议利用在胚胎发育中起关键作用的雌激素应答HOX基因的启动子。最近，我们发现雌激素（E2）对包括HOXC 13和旁系同源基因（HOXA 13，B13和D13）在内的几个HOX基因进行转录调控。HOXC13启动子包含多个雌激素反应元件（EREs），雌激素受体（ER：ER α和ER μ）在E2介导的基因激活期间与所述EREs结合。重要的是，我们还发现，混合谱系白血病（MLL）家族的组蛋白甲基转移酶是基因激活的关键参与者，与ER相互作用并结合这些ER，以调节HOXC 13在E2存在下的表达。基于这些发现，我们假设HOXC13和旁系同源基因受ER和MLL（作为辅助调节因子）调节。在此，我们建议研究E2介导的HOXC13和旁系同源基因转录调控的表观遗传调控机制，并扩展这一知识，以开发新的基于细胞的测定方法，以评估各种已知和未知的内分泌干扰活性，并了解其作用机制。此外，我们亦建议透过服务学习，向社会推广有关内分泌干扰物的知识。这些研究将揭示E2介导的HOX基因调控的表观遗传学调控机制。此外，这些研究将提供有关EDCs作用的新见解，并提供新的测定方法来评估各种已知和未知EDCs的内分泌干扰活性。外展活动将提高当地社区对内分泌干扰物及其与人类健康和社会的相关性的认识，这将对人类健康质量产生重大影响，并可能降低癌症和其他疾病的发病率。 公共卫生相关性：内分泌干扰化学品（EDCs）是一种模仿激素并干扰正常激素功能的化学品，对生殖，行为和发育产生不利影响，最终导致严重的人类疾病，包括癌症。在此，提出实验以a）评估各种已知和未知的EDCs的内分泌干扰活性，B）了解它们的作用机制和c）向社区推广以提高对EDCs的认识。这些研究将对人类的生活质量和健康产生重大影响，并可能长期降低癌症和其他疾病的发病率。

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.