Effects of fetal bisphenol A exposure on mouse epigenome

胎儿双酚 A 暴露对小鼠表观基因组的影响

• 批准号: 8424594
• 负责人: Martha Susiarjo
• 金额: $ 9.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-18 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424594
• 关键词: Adult; Affect; Animal Model; Behavior; Biological Models; Biological Process; Brain; Cell Cycle; DNA; DNA Methylation; Data; Defect; Development; Developmental Gene; Disease; EZH2 gene; Embryo; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Etiology; Fetal Development; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genomic Imprinting; Goals; Growth and Development function; Health; Histones; Human; Immune system; Immunoprecipitation; Infertility; Laboratories; Link; Malignant Neoplasms; Mediating; Methylation; Modification; Molecular; Molecular Profiling; Mus; Newborn Infant; Nucleic Acid Regulatory Sequences; Nutrient; Obesity; Pathway interactions; Pattern; Phenotype; Placenta; Placentation; Plasticizers; Plastics; Play; Predisposition; Public Health; Regulation; Reporting; Reproduction; Research; Risk Management; Role; Signal Transduction; Testing; Tissues; Work; bisphenol A; bisulfite; brain metabolism; chromatin immunoprecipitation; developmental disease; epigenome; epigenomics; fetal; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; gene function; genome wide methylation; genome-wide; histone methyltransferase; histone modification; human disease; imprint; in utero; inhibitor/antagonist; insight; interest; postnatal; prenatal exposure; protein expression; public health relevance; receptor

DESCRIPTION (provided by applicant): Increasing evidence has shown that environmental exposures cause various developmental abnormalities. Elucidation of the relevant molecular pathways provides critical insights into risks management and preventative approaches. A compound that has created a great public health concern is bisphenol A (BPA), commonly used in various plastic products. Humans are widely exposed and exposure is linked to obesity, infertility, cancer, reduced immune system and behavior anomalies in model organisms. Despite the widely reported phenotypes induced by BPA exposure, the relevant molecular mechanisms are unclear. Recently, several laboratories have demonstrated the ability of BPA to alter DNA methylation, proposing that epigenetic mechanisms are involved in BPA developmental action. The candidate's work has found effects of BPA exposure on the expression and methylation of mouse imprinted loci. As imprinted loci are critical for fetal, placental and postnatal brain development, and disrupted functions are linked to human developmental disorders, work demonstrates that fetal BPA exposure has the potential to impact development through epigenetic perturbations of developmental genes. In the current application, genome wide methylation and expression studies in the embryonic and placental tissues of mice exposed prenatally to BPA will be undertaken using methylated DNA immunoprecipitation followed by sequencing and using microarrays, respectively. The goal is to identify the relevant epigenetic pathways. The candidate will include mice lacking the functional genes for estrogen receptor alpha and beta as BPA is an estrogen and the project aims to investigate if these receptors mediate BPA effects in the epigenome. Additionally, the candidate proposes to study the effects of BPA exposure in placental development as her previous studies revealed significant epigenetic dysregulation of the imprinted Cdkn1c gene. The cell cycle inhibitor Cdkn1c gene plays a critical role in mouse placental development and histological and immunohistochemical studies will be conducted to analyze placentas from BPA-exposed mice. The current application also proposes to investigate the genome wide and gene specific roles of the histone methyltransferase EZH2 and its relevant H3K27me3 histone mark in mediating BPA-induced developmental abnormalities as several laboratories have found aberrant expression of the proteins in various tissues from mice exposed in utero to BPA. These studies will utilize chromatin immunoprecipitation followed by sequencing or followed by qPCR.

描述（由申请人提供）：越来越多的证据表明环境暴露会导致各种发育异常。相关分子途径的阐明为风险管理和预防方法提供了重要的见解。双酚 A (BPA) 是一种引起重大公共卫生问题的化合物，常用于各种塑料产品中。人类广泛暴露于该物质，并且暴露与模型生物的肥胖、不孕、癌症、免疫系统降低和行为异常有关。尽管 BPA 暴露诱发的表型已被广泛报道，但相关的分子机制尚不清楚。最近，一些实验室证明了 BPA 改变 DNA 甲基化的能力，提出表观遗传机制参与了 BPA 的发育作用。该候选人的工作发现了 BPA 暴露对小鼠印迹基因座的表达和甲基化的影响。由于印记位点对于胎儿、胎盘和产后大脑发育至关重要，而功能紊乱与人类发育障碍有关，因此研究表明，胎儿 BPA 暴露有可能通过发育基因的表观遗传扰动影响发育。在目前的应用中，将使用甲基化DNA免疫沉淀法，然后分别进行测序和使用微阵列，对产前暴露于BPA的小鼠的胚胎和胎盘组织进行全基因组甲基化和表达研究。目标是确定相关的表观遗传途径。该候选项目将包括缺乏雌激素受体α和β功能基因的小鼠，因为BPA是一种雌激素，该项目旨在研究这些受体是否介导表观基因组中的BPA效应。此外，该候选人提议研究 BPA 暴露对胎盘发育的影响，因为她之前的研究揭示了印记 Cdkn1c 基因的显着表观遗传失调。细胞周期抑制剂 Cdkn1c 基因在小鼠胎盘发育中发挥着关键作用，将进行组织学和免疫组织化学研究来分析 BPA 暴露小鼠的胎盘。当前的申请还建议研究组蛋白甲基转移酶 EZH2 及其相关 H3K27me3 组蛋白标记在介导 BPA 诱导的发育异常中的全基因组和基因特异性作用，因为一些实验室已发现子宫内暴露的小鼠的各种组织中蛋白质的异常表达双酚A。这些研究将利用染色质免疫沉淀，然后进行测序或 qPCR。