Early Life Exposure to Endocrine-Disrupting Chemicals Causes Lifelong Molecular Reprogramming of the Hypothalamus and Premature Reproductive Aging
Early Life Exposure to Endocrine-Disrupting Chemicals Causes Lifelong Molecular Reprogramming of the Hypothalamus and Premature Reproductive Aging
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DOI：
10.1210/me.2011-1210
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发表时间：
2011-12-01
影响因子：
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通讯作者：
Uzumcu, Mehmet
中科院分区：
文献类型：
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作者：
Gore, Andrea C.;Walker, Deena M.;Uzumcu, Mehmet
孕期暴露于雌激素内分泌干扰物甲氧滴滴涕（MXC）会在成年期从分子、生理和行为层面扰乱雌性生殖系统。本研究探讨了围产期暴露于内分泌干扰物是否会重新编程下丘脑中表达的一组控制生殖功能的基因的表达，并将这些分子变化与生殖过早衰老相关联。从胚胎第19天到出生后第7天，费舍尔大鼠连续12天每天分别暴露于溶媒（二甲基亚砜）、苯甲酸雌二醇（EB）（1毫克/千克）和MXC（低剂量，20微克/千克或高剂量，100毫克/千克）。围产期暴露的雌性大鼠饲养至16 - 17个月，并监测其生殖衰老情况。处死后，解剖下丘脑区域[视前区（POA）和内侧基底下丘脑]，用于基因表达的实时定量PCR或焦磷酸测序，以评估Esr1基因的DNA甲基化。使用48基因PCR平台，经过邦费罗尼校正后，与溶媒暴露的大鼠相比，内分泌干扰化学物暴露的大鼠的视前区中有两个基因（Kiss1和Esr1）存在显著差异。与溶媒相比，EB或高剂量MXC使15个视前区基因上调至少50%。为了解Esr1基因表达增加的表观遗传学基础，我们对Esr1启动子进行了亚硫酸氢盐转化和焦磷酸测序。与对照大鼠相比，EB处理的大鼠在Esr1启动子的三个CpG位点的甲基化百分比显著更高。连同这些分子效应，围产期MXC和EB改变了发情周期并加速了生殖衰老。因此，生命早期暴露于内分泌干扰物对神经内分泌基因表达和DNA甲基化具有终身影响，同时导致生殖衰老提前。（《分子内分泌学》25:2157 - 2168，2011）
Gestational exposure to the estrogenic endocrine disruptor methoxychlor (MXC) disrupts the female reproductive system at the molecular, physiological, and behavioral levels in adulthood. The current study addressed whether perinatal exposure to endocrine disruptors reprograms expression of a suite of genes expressed in the hypothalamus that control reproductive function and related these molecular changes to premature reproductive aging. Fischer rats were exposed daily for 12 consecutive days to vehicle (dimethylsulfoxide), estradiol benzoate (EB) (1 mg/kg), and MXC (low dose, 20 mu g/kg or high dose, 100 mg/kg), beginning on embryonic d 19 through postnatal d 7. The perinatally exposed females were aged to 16-17 months and monitored for reproductive senescence. After euthanasia, hypothalamic regions [ preoptic area (POA) and medial basal hypothalamus] were dissected for real-time PCR of gene expression or pyrosequencing to assess DNA methylation of the Esr1 gene. Using a 48-gene PCR platform, two genes (Kiss1 and Esr1) were significantly different in the POA of endocrine-disrupting chemical-exposed rats compared with vehicle-exposed rats after Bonferroni correction. Fifteen POA genes were up-regulated by at least 50% in EB or high-dose MXC compared with vehicle. To understand the epigenetic basis of the increased Esr1 gene expression, we performed bisulfite conversion and pyrosequencing of the Esr1 promoter. EB-treated rats had significantly higher percentage of methylation at three CpG sites in the Esr1 promoter compared with control rats. Together with these molecular effects, perinatal MXC and EB altered estrous cyclicity and advanced reproductive senescence. Thus, early life exposure to endocrine disruptors has lifelong effects on neuroendocrine gene expression and DNA methylation, together with causing the advancement of reproductive senescence. (Molecular Endocrinology 25:2157-2168, 2011)