Effects of Bisphenol A Exposure on Genomic Imprinting in the Mouse

双酚 A 暴露对小鼠基因组印记的影响

基本信息

批准号：
8113986
负责人：
Martha Susiarjo
金额：
$ 5.47万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2013-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113986
关键词：
Address Affect Alleles Angelman Syndrome Animals Beckwith-Wiedemann Syndrome Beverages Binding Biological Assay Chemicals DNA DNA Methylation Defect Development Disease Dose Embryo Environment Epigenetic Process Estrogen Receptor alpha Estrogen Receptors Estrogens Etiology Exposure to Fetus Food Gene Expression Gene Expression Regulation Genes Genomic Imprinting Goals Growth and Development function Health Human Investigation Laboratories Laboratory Animals Link Mammals Mediating Methylation Molecular Molecular Profiling Mus Mutagenesis Mutant Strains Mice Neonatal Newborn Infant Nutrient Parents Pathway interactions Pattern Pit and Fissure Sealants Plant Resins Play Prader-Willi Syndrome Production Property Regulation Research Reverse Transcription Role Safety Sampling Silver-Russell syndrome System Testing Tissues Vulnerable Populations Work base bisphenol A bisulfite fetal gene repression genome-wide human disease imprint in utero insight mammalian genome neonate polycarbonate plastic postnatal pregnant prenatal prenatal exposure promoter public health relevance research study

项目摘要

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.

描述（由申请人提供）：这项工作的目标是确定双酚 A (BPA) 是否会扰乱早期哺乳动物发育过程中的表观遗传基因调控。 BPA 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、树脂基产品和牙科密封剂。人类普遍接触双酚 A；胎儿和新生儿由于无法有效代谢 BPA，因此最容易受到伤害。这些观察结果令人震惊，因为实验动物胎儿和产后早期发育期间的低剂量暴露与各种健康异常有关。尽管 BPA 诱导的作用被认为是由其类雌激素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 暴露已被证明会通过 DNA 甲基化的改变引起小鼠的表观遗传变化，尽管这项工作是初步的，需要进一步研究。拟议的研究最初将集中于印记基因，因为这些基因受到表观遗传调控。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至关重要。印记基因的异常表达和调节与许多人类疾病有关，包括贝克威斯-维德曼综合症、普瑞德-威利综合症、天使曼综合症和西尔弗-拉塞尔综合症。初步实验还表明，接触 BPA 会导致印记基因表达失调，并减少部分基因座的 DNA 甲基化。该提案将进一步研究暴露于不同剂量和不同发育窗口期的 BPA 对小鼠胎儿和怀孕小鼠的新生儿的印记基因表达和甲基化的影响。此外，还将通过全球启动子甲基化和基因表达研究来调查 BPA 暴露对全基因组的影响。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，并评估对表观遗传基因调控的影响。除了提供 BPA 作用的一般机制见解外，拟议的工作还将具体阐明具有潜在环境原因的印记疾病的潜在病因。公共健康相关性：拟议的研究将调查接触环境相关化学物质双酚 A (BPA) 是否会破坏对正常哺乳动物生长和发育至关重要的印记基因的表观遗传调控。该小鼠系统将用于阐明与 BPA 引起的健康异常相关的分子机制，并确定具有潜在环境原因的人类疾病的潜在病因。