Effects of Bisphenol A Exposure on Genomic Imprinting in the Mouse

描述(申请人提供)：这项工作的目标是确定双酚A(BPA)是否扰乱哺乳动物早期发育过程中的表观遗传基因调控。双酚A是全球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、树脂产品和牙科密封剂。人类无处不在地接触到双酚A；胎儿和新生儿由于无法有效代谢双酚A而最容易受到伤害。这些观察结果令人担忧，因为在实验动物的胎儿和出生后早期发育过程中，低剂量暴露与各种健康异常有关。虽然BPA的诱导效应被认为是由于其雌激素样特性和与雌激素受体结合的能力而产生的，但确切的分子机制尚不清楚。最近，双酚A暴露被证明通过改变DNA甲基化而导致小鼠的表观遗传学变化，尽管这项工作是初步的，需要进一步的研究。拟议的研究最初将专注于印记基因，因为这些基因是表观遗传调控的。印记基因以及适当的印记基因表达模式对于哺乳动物的正常生长和发育是必不可少的。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。初步实验还证明，暴露于双酚A会导致印迹基因的错误表达，并减少部分基因座的DNA甲基化。这项建议将进一步研究暴露于不同剂量和不同发育窗口的双酚A对小鼠胎儿和怀孕小鼠新生儿印迹基因表达和甲基化的影响。此外，将通过全球启动子甲基化和基因表达研究来研究双酚A暴露对全基因组的影响。为了解决雌激素受体是否介导双酚A诱导效应的问题，缺乏雌激素受体α和β功能基因的小鼠将暴露于双酚A，并将评估其对表观基因调控的影响。除了提供对双酚A作用的一般机械洞察外，拟议的工作还将具体阐明印记疾病的潜在病因学和潜在的环境原因。 与公共健康相关：拟议的研究将调查暴露于与环境相关的化学物质双酚A(BPA)是否扰乱了印记基因的表观遗传调控，印记基因对哺乳动物的正常生长和发育至关重要。小鼠系统将被用来阐明与双酚A诱导的健康异常相关的分子机制，并确定人类疾病的潜在病因学和潜在的环境原因。

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.