Meiotic Studies of Chemicals With Estrogenic Activity

描述（由申请人提供）：非整倍体，染色体的丢失或获得，是人类怀孕失败和出生缺陷的主要原因。大多数非整倍体是由母体不分离引起的，但其病因尚不清楚。长期以来，人们一直怀疑环境因素起着一定的作用，但直到最近，这一观点还没有得到直接证据的证实。我们实验室最近的研究表明，在怀孕期间暴露于雌激素化学物质双酚A （BPA）会显著增加小鼠染色体异常卵子和胚胎的频率。因为人类每天都暴露在BPA中，这些发现对人类生殖健康有着严重的影响。本申请中概述的研究将使用小鼠模型来测试胎儿BPA暴露对雌性生殖寿命的影响，并研究BPA对卵子发生早期阶段的影响机制。此外，我们将通过直接研究人类胎儿卵母细胞来将我们的发现从小鼠转化为人类，以确定BPA是否同样影响人类的早期卵发生。最后，我们将测试遗传变异对生物活性双酚a到达特定组织的能力和组织对双酚a的反应的影响。这些研究的综合数据将增强我们对这种化学物质对人类生育能力构成的风险的理解。

DESCRIPTION (provided by applicant): Aneuploidy, the loss or gain of chromosomes, is the leading cause of human pregnancy failure and birth defects. Most aneuploidy arises from maternal nondisjunction, but its etiology remains obscure. Environmental factors have long been suspected to play a role but, until recently, this has not been substantiated by direct evidence. Recent studies in our laboratory suggest that exposure to the estrogenic chemical, bisphenol A (BPA) during pregnancy dramatically increases the frequency of chromosomally abnormal eggs and embryos in the mouse. Because humans are exposed to BPA on a daily basis, these findings have serious implications for human reproductive health. The studies outlined in this application will use mouse models to test the effects of fetal BPA exposure on reproductive lifespan in the female and examine the mechanisms by which BPA exerts its effects on the early stages of oogenesis. In addition, we will translate our findings from mice to humans by directly studying human fetal oocytes to determine if BPA similarly impacts early oogenesis in humans. Lastly, we will test the effect of genetic variation on the ability of biologically active BPA to reach specific tissues and on the tissue response to BPA. The combined data from these studies will enhance our understanding of the risk to human fertility posed by this chemical. PUBLIC HEALTH RELEVANCE: These studies will assess the effects on human reproductive health of bisphenol A (BPA), a member of a class of chemicals known as endocrine disrupting chemicals. Specifically, the studies outlined in this application focus on BPA-induced effects on gametogenesis in female mice and - for the first time - directly address the possibility that BPA exposure affects gamete production in humans as well.