Epigenetic effects if endocrine disruptors in fetal germ cells

描述(由申请人提供)： 一些非遗传毒性药物会引起表观遗传变化，包括异常的DNA甲基化。这些药物的一个子集被称为内分泌干扰剂-类似于自然荷尔蒙的合成化学物质-对发育和生育有深远的影响。该提案的中心假设是，发育中的生殖细胞经历了全基因组的表观遗传重新编程，特别容易受到内分泌干扰物的表观遗传效应的影响。胎儿生殖细胞为揭示跨代表观遗传效应的起源提供了一个很好的研究系统。这项建议旨在确定胎儿生殖细胞在宫内暴露于选定的内分泌干扰物后的表观遗传学变化。为了解决中心假设，具体目标是：1)确定胎儿暴露于内分泌干扰物后围产期生殖细胞中H19/lgf2印记控制区(ICR)的甲基化状态；2)评估内分泌干扰物在胎儿生殖细胞和性腺体细胞中引起的全球转录变化；以及3)确定内分泌干扰物在小鼠雌性和雄性生殖细胞中异常高甲基化的靶点。

DESCRIPTION (provided by applicant): Some non-genotoxic agents cause epigenetic changes, including aberrant DNA methylation. A subset of these drug, called endocrine disrupters -synthetic chemicals resembling natural hormones-, have profound effects on development and fertility. The central hypothesis of the proposal is that developing germ cells, which undergo genome-wide epigenetic reprogramming, are especially vulnerable to the epigenetic effects of endocrine disrupters. Fetal germ cells provide an excellent study system to reveal the origin of transgenerational epigenetic effects. This proposal seeks to identify epigenetic changes in fetal germ cells after intrauterine exposure to selected endocrine disrupters. To address the central hypothesis, the specific aims are to: 1) Determine the methylation status of the H19/lgf2 imprinting control region (ICR) in perinatal germ cells after fetal exposure to endocrine disrupting chemicals; 2) Assess global transcription changes caused by endocrine disrupters in fetal germ cells and gonadal somatic cells; and 3) Identify targets for aberrant hypermethylation by endocrine disrupters, in mouse female and male germ cells.