Epigenetic Marks of Xenoestrogen Exposure

描述（由申请人提供）：本申请涉及广泛的挑战领域（08）基因组学和特定的挑战主题08-ES-104，鉴定与环境暴露相关的表观遗传标记的改变。在环境中接触具有雌激素活性的外来化学品的情况很普遍，并被认为会对人类健康产生不利影响。接触这些异种雌激素和其他干扰内分泌的化学品与各种发育和生殖异常有关，人类和其他物种在胚胎、胎儿和出生后早期的关键时期对内分泌活性化合物过敏。该项目的总体目标是调查以下假设：围产期暴露于异种雌激素会诱导与控制女性生殖道发育的关键基因表达的永久性变化相关的表观遗传标记，而这些变化又与观察到的生殖道异常和子宫癌发病率增加有关。有人提出，每种异种雌激素具有独特的表观遗传特征，这是由于其作为选择性雌激素受体调节剂的独特活性。将使用暴露于异种雌激素己烯雌酚和双酚A的子宫内小鼠模型来检验这些假设。己烯雌酚是一种强效的异种雌激素，与小鼠模型和暴露于该物质的人类的主要生殖道发育异常有关，而双酚A是一种弱异种雌激素，在小鼠中诱导较温和的生殖毒性;人类暴露于后一种化学品的后果尚未明确确定。发现表观遗传签名是共同的，以及那些是独特的，每种异种雌激素将有助于阐明生殖毒理学与每种化学品。这些研究将为内分泌活性环境化学品诱导生殖毒性的机制提供重要的新见解，并可能最终导致检测和预防接触者不良影响的新战略。拟议的研究的意义是重大的，无论是在新的科学知识，预计结果，并对大量的个人暴露于环境异种雌激素的潜在影响。经济刺激的影响预计也将是重大的，通过直接雇用研究人员来支持该项目的需要，并通过实验室研究用品资金的支出产生积极的经济刺激，推进复苏法案的目标。 公共卫生相关性：该项目调查环境化学品对生殖系统的毒性作用，特别强调环境雌激素对人类和其他暴露的哺乳动物的雌性生殖系统的毒性。所提议的研究将为内分泌活性环境化学品诱导生殖毒性的机制提供重要的新见解，并可能最终导致检测和预防接触者不良影响的新战略。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic 08-ES-104, Identification of Alterations in Epigenetic Marks Related to Environmental Exposures. Environmental exposure to foreign chemicals with estrogenic activities is widespread and is proposed to impact adversely on human health. Exposure to these xenoestrogens and other endocrine-disrupting chemicals has been associated with a variety of developmental and reproductive abnormalities, with humans and other species being hypersensitive to endocrine-active compounds during critical periods of embryonic, fetal and early postnatal life. The overall goal of this project is to investigate the hypothesis that perinatal exposure to xenoestrogens induces epigenetic marks associated with permanent changes in expression of key genes controlling female reproductive tract development, which are, in turn, linked to the observed reproductive tract abnormalities and increased incidence of uterine cancer. It is proposed that each xenoestrogen has a unique epigenetic signature as a result of its unique activity as a selective estrogen receptor modulator. These hypotheses will be tested using in utero mouse models of exposure to the xenoestrogens diethylstilbestrol and bisphenol-A. Diethylstilbestrol is a potent xenoestrogen linked to major reproductive tract developmental abnormalities in mouse models and in exposed humans, while bisphenol-A is a weak xenoestrogen that induces more modest reproductive toxicities in the mouse; the consequences of human exposure to the latter chemical are not definitively established. Discovery of the epigenetic signatures that are common, as well as those that are unique, to each xenoestrogen will help elucidate the reproductive toxicology associated with each chemical. These studies will provide important new insight into the mechanisms through which endocrine-active environmental chemicals induce reproductive toxicities, and may, ultimately, lead to new strategies for detection and prevention of adverse effects in exposed individuals. The significance of the studies proposed is major, both in terms of the new scientific knowledge that is expected to result, and for the potential impact on the large number of individuals that are exposed to environmental xenoestrogens. The economic stimulatory impact is also expected to be major, advancing Recovery Act goals through the direct hiring of research staff to support the needs of this project and via the positive economic stimulus that will result from the expenditure of laboratory research supplies funds. PUBLIC HEALTH RELEVANCE: This project investigates the actions of environmental chemicals that exert reproductive toxicities, with special emphasis on environmental estrogens that induce female reproductive tract toxicities in humans and other exposed mammals. The studies that are proposed will provide important new insight into the mechanisms through which endocrine-active environmental chemicals induce reproductive toxicities, and may, ultimately, lead to new strategies for detection and prevention of adverse effects in exposed individuals.