Effects of Bisphenol A Exposure on Genomic Imprinting in the Mouse

描述（由申请人提供）：这项工作的目的是确定双酚A （BPA）是否会干扰哺乳动物早期发育过程中的表观遗传基因调控。BPA是世界上产量最高的化学品之一，用于生产聚碳酸酯塑料、食品和饮料包装、树脂基产品和牙科密封剂。人类无处不在地暴露于BPA；胎儿和新生儿是最脆弱的，因为他们不能有效地代谢BPA。这些观察结果令人震惊，因为实验动物在胎儿和出生后早期发育期间的低剂量暴露与各种健康异常有关。尽管双酚a诱导的作用被认为是由其雌激素样特性和与雌激素受体结合的能力引起的，但确切的分子机制尚不清楚。最近，BPA暴露已被证明通过改变DNA甲基化引起小鼠的表观遗传变化，尽管这项工作是初步的，需要进一步的研究。拟议的研究最初将集中在印迹基因上，因为这些基因是表观遗传调控的。印迹基因以及适当的印迹基因表达模式对哺乳动物的正常生长发育至关重要。印迹基因的异常表达和调控与许多人类疾病有关，包括Beckwith-Wiedemann综合征、Prader-Willi综合征、Angelman综合征和Silver-Russell综合征。初步实验还表明，BPA暴露会导致印记基因表达失调，并减少部分位点的DNA甲基化。本研究将进一步研究不同剂量和不同发育窗口期BPA暴露对小鼠胎儿和新生儿印迹基因表达和甲基化的影响。此外，BPA暴露的全基因组后果将通过全球启动子甲基化和基因表达研究进行调查。为了解决雌激素受体是否介导BPA诱导效应的问题，将缺乏雌激素受体α和β功能基因的小鼠暴露于BPA并评估其对表观遗传基因调控的影响。除了提供双酚a作用的一般机制见解外，拟议的工作将特别阐明具有潜在环境原因的印迹疾病的潜在病因。

DESCRIPTION (provided by applicant): The goal of this work is to determine whether bisphenol A (BPA) perturbs epigenetic gene regulation during early mammalian development. BPA is one of the most highly produced chemicals worldwide used in the production of polycarbonate plastics, food and beverage packaging, resin-based products and dental sealant. Humans are ubiquitously exposed to BPA; fetuses and neonates are most vulnerable due to their inability to metabolize BPA efficiently. These observations are alarming as low dose exposure during fetal and early postnatal development in laboratory animals has been associated with various health abnormalities. Although BPA-induced effects are thought to arise from its estrogen-like properties and ability to bind to estrogen receptors, the exact molecular mechanisms are unclear. Recently, BPA exposure has been shown to cause epigenetic changes in the mouse through alteration in DNA methylation, although the work is preliminary and requires further investigation. The proposed research will initially focus on imprinted genes, as these genes are epigenetically regulated. Imprinted genes, as well as appropriate imprinted gene expression patterns, are essential for normal growth and development in mammals. Aberrant expression and regulation of imprinted genes is associated with a number of human diseases, including Beckwith-Wiedemann Syndrome, Prader-Willi Syndrome, Angelman Syndrome and Silver-Russell Syndrome. Preliminary experiments have also demonstrated that BPA exposure results in misregulated imprinted gene expression and reduced DNA methylation at a subset of loci. This proposal will further examine the effect of exposure on imprinted gene expression and methylation in mouse fetuses and newborns of pregnant mice exposed to BPA at various doses and during different developmental windows. Additionally, the genome-wide consequences of BPA exposure will be investigated through global promoter methylation and gene expression studies. To address the question of whether estrogen receptors mediate BPA-induced effects, mice lacking functional genes for the estrogen receptor alpha and beta will be exposed to BPA and the effects on epigenetic gene regulation will be assessed. In addition to providing general mechanistic insights into BPA actions, the proposed work will specifically elucidate the potential etiology of imprinting diseases with underlying environmental causes. PUBLIC HEALTH RELEVANCE: The proposed research will investigate whether exposure to the environmentally relevant chemical bisphenol A (BPA) disrupts the epigenetic regulation of imprinted genes that are critical for normal mammalian growth and development. The mouse system will be used to elucidate molecular mechanisms related to BPA-induced health abnormalities and to determine the potential etiology of human diseases with underlying environmental causes.