Epigenetic and Behavioral Effects of BPA Exposure

描述(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年人类的血液中。暴露在这种内分泌活性化合物中会改变正常的荷尔蒙功能，影响神经组织，最终可能会改变行为，导致神经障碍。双酚A可能的作用机制之一是通过减少DNA甲基化导致基因表达失调。我将确定子宫内双酚A暴露后的持续性、表观遗传学和行为变化。BPA诱导的低甲基化的确切靶点和/或其对基因转录的影响尚未完全确定。在这些研究中，我将使用与人类相同的剂量的双酚A，并通过母体饮食暴露小鼠胚胎。在目标1中，将使用全基因组甲基组图谱来识别双酚A在这些小鼠发育中的大脑中诱导的变化。我将使用亚硫酸氢盐测序在DNA甲基化水平上确认表观遗传学变化，并测量协调变化的基因表达。在此基础上，我将创建一个用于验证的优先基因列表。在我们的模型中，双酚A暴露降低了雌激素受体α的甲基化。为了直接确定与双酚A暴露相关的变化相关的表观遗传修饰，在第二个目标中，我将测试在对照或双酚A饮食中怀孕的雌激素受体α基因敲除小鼠的青少年社会行为变化。这些研究将有助于识别双酚A的分子靶标，并有可能发现表观遗传改变导致行为改变的基因。 与公众健康相关：双酚A(BPA)是一种用于塑料制造的人造化学物质，存在于饮用水和塑料产品中，如婴儿奶瓶、食品罐头衬里和牙科密封剂。它耐降解，因此是从垃圾填埋场渗入水中的主要雌激素化合物，积聚在人体血液中。在发育中的大脑中接触双酚A可能会在表观遗传学上改变某些与神经和行为疾病相关的基因的表达。通过研究双酚A在发育中的小鼠的行为和表观遗传学效应，我们希望确定与人类神经发育疾病相关的表观遗传学变化。

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.