Meiotic Studies of Chemicals With Estrogenic Activity

描述(申请人提供)：非整倍体，即染色体的丢失或获得，是人类妊娠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在起作用，但直到最近，这一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，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发生率。由于人类每天都接触到双酚A，这些发现对人类生殖健康具有严重影响。本申请概述的研究将使用小鼠模型来测试胎儿双酚A暴露对雌性生殖寿命的影响，并研究双酚A在卵子发生的早期阶段发挥作用的机制。此外，我们将通过直接研究人类胚胎卵母细胞，将我们的发现从小鼠转移到人类，以确定BPA是否类似地影响人类的早期卵子发生。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以及组织对双酚A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.