EPIGENETIC EFFECT OF METHOXYCHLOR ON OVARIAN DEVELOPMENT

描述（由申请人提供）：本提案的主要目的是了解胎儿/新生儿卵巢发育期间内分泌干扰物甲氧滴滴涕（MXC）暴露的延迟表观遗传效应。表观遗传改变（例如，DNA甲基化）导致异常基因表达，这可能导致重大疾病，如癌症。胎儿/新生儿暴露于雌激素性内分泌干扰物会导致成年人的子宫和睾丸异常，这些异常与DNA甲基化变化有关。卵巢中是否发生类似的表观遗传效应尚不清楚。假设胎儿/新生儿发育期间短暂的MXC暴露通过改变早期卵泡发生、DNA甲基化和基因表达直接损害成年卵巢功能。有三个具体目标来检验这个假设。具体目的1是确定胎儿/新生儿卵巢发育期间MXC暴露对成人卵巢功能、形态、DNA甲基化和基因表达的影响（成人效应）。大鼠将在围产期接受MXC给药。将评估青春期年龄和成年卵巢功能，如对促性腺激素的反应、生育力、窝仔数和早期衰老。DNA甲基化和关键基因表达（例如，星星、P450 SCC、LHR）进行成人卵巢功能检查。具体目的2是确定MXC的成人效应是否由胎儿/新生儿卵巢中卵泡发生、DNA甲基化和基因表达的改变引起（成人效应的胎儿基础）。将使用器官培养检查早期卵泡发生、DNA甲基化和卵巢发育的关键基因表达（bFGF、GDF-9、MIS）。具体目的3是确定早期MXC暴露是否直接影响器官移植的卵巢（直接效应）。这项建议是调查是否短暂围产期暴露于内分泌干扰物MXC直接改变成年卵巢功能。这一发现将提高我们对表观遗传性成人卵巢功能障碍的胎儿基础的理解。

DESCRIPTION (provided by applicant): The broad objective of this proposal is to understand the delayed epigenetic effect of endocrine disrupter methoxychlor (MXC) exposure during fetal/neonatal ovarian development. Epigenetic alterations (e.g., DNA methylation) cause aberrant gene expression, which can lead to major diseases such as cancer. Fetal/ neonatal exposure to estrogenic endocrine disrupters results in uterine and testicular abnormalities in the adult that are linked to DNA methylation changes. Whether similar epigenetic effects occur in the ovary is unknown. The HYPOTHESIS is that transient MXC exposure during fetal/neonatal development directly impairs adult ovarian function by altering early folliculogenesis, DNA methylation, and gene expression. There are 3 specific aims to test this hypothesis. SPECIFIC AIM 1 is to identify the effect of MXC exposure during fetal/neonatal ovarian development on adult ovarian function, morphology, DNA methylation, and gene expression (adult effect). Rats will be treated with MXC perinatally. Pubertal age and adult ovarian functions such as response to gonadotropins, fertility, litter size, and early aging will be assessed. DNA methylation and critical gene expression (e.g., StAR, P450scc, LHR) for adult ovarian function will be examined. SPECIFIC AIM 2 is to determine if the adult effect of MXC results from alterations in folliculogenesis, DNA methylation and gene expression in the fetal/neonatal ovary (fetal basis of adult effect). Early folliculogenesis, DNA methylation, and critical gene expression for ovarian development (bFGF, GDF-9, MIS) will be examined using organ culture. SPECIFIC AIM 3 is to determine whether early MXC exposure directly affects the ovary using organ transplantation (direct effect). This proposal is to investigate whether transient perinatal exposure to the endocrine disrupter MXC directly alters adult ovarian function. The findings will improve our understanding of the fetal basis of epigenetic adult ovarian dysfunction.