Epigenetic and Behavioral Effects of BPA Exposure

描述（由申请人提供）：双酚A （BPA）是一种主要的环境破坏化合物，在作为增塑剂使用了几十年后，它存在于几乎所有发育中和成人的血液中。暴露于这种内分泌活性化合物会改变正常的激素功能，影响神经组织，最终改变行为并导致神经系统疾病。BPA可能起作用的一种机制是通过减少DNA甲基化导致基因表达失调。我将确定子宫内BPA暴露后的持续、表观遗传和行为变化。bpa诱导的低甲基化和/或其对基因转录的影响的确切目标尚未完全表征。在这些研究中，我将使用与人类相同剂量的双酚a，并通过母体饮食暴露小鼠胚胎。在Aim 1中，将使用全基因组甲基组分析来鉴定这些小鼠发育中的大脑中bpa诱导的变化。我将在DNA甲基化水平上使用亚硫酸盐测序来确认表观遗传变化，并测量一致性改变基因表达。从这里，我将创建一个优先的基因列表进行验证。在我们的模型中，BPA暴露会降低雌激素受体α的甲基化。为了直接确定与BPA暴露相关的表观遗传修饰，在第二个目标中，我将测试雌激素受体α敲除小鼠在对照组或BPA饮食中妊娠的幼年社会行为的变化。这些研究将有助于确定BPA的分子目标，并有可能揭示导致行为改变的表观遗传改变的基因。

DESCRIPTION (provided by applicant): Bisphenol A (BPA) is a major environmental disruptor compound and after several decades in use as a plasticizer it is present in the blood of nearly all developing and adult humans. Exposure to this endocrine- active compound alters normal hormonal function, affects neural organization and ultimately can modify behavior and lead to neurological disorders. One mechanism by which BPA may act is via decreased DNA methylation causing dysregulated gene expression. I will identify persistent, epigenetic and behavioral changes following in utero BPA exposure. The exact targets of BPA-induced hypomethylation and/or its effects on gene transcription have not been fully characterized. In these studies, I will use a dose of BPA equivalent to that noted in humans and expose mouse embryos via maternal diet. BPA-induced changes in the developing brain of these mice will be identified using genome-wide methylome profiling in Aim 1. I will confirm the epigenetic changes at the level of DNA methylation using bisulfite sequencing and measure the concordant altered gene expression. From this, I will create a prioritized gene list for validation. In our model, BPA exposure decreases methylation of estrogen receptor alpha. In order to directly identify epigenetic modifications relevant to changes associated with BPA exposure, in the second aim, I will test estrogen receptor alpha knockout mice gestated on control or BPA diets for alterations in juvenile social behaviors. These studies will aid in the identification of BPA's molecular targets and potentially uncover genes that are epigenetically changed leading to altered behavior. PUBLIC HEALTH RELEVANCE: Bisphenol A (BPA) is a man-made chemical used in plastic manufacturing and is present in drinking water and plastic products such as baby bottles, food can linings and dental sealants. It is resistant to degradation and thus is the major estrogenic compound that leaches from landfills into the water supply accumulating in human blood. BPA exposure in the developing brain may epigenetically alter the expression of certain genes relevant to neurological and behavioral diseases. By studying BPA's behavioral and epigenetic effects in a developing mouse, we hope to identify pertinent epigenetic changes relevant to human neurodevelopmental disease.