a Department of Environmental Health , University of Cincinnati College of Medicine , Cincinnati , OH , USA.
b Center for Environmental Genetics , Department of Environmental Health, University of University of Cincinnati College of Medicine , Cincinnati , OH , USA.
Epigenetics. 2018;13(7):704-720. doi: 10.1080/15592294.2018.1497388. Epub 2018 Aug 15.
Bisphenol A (BPA), an endocrine disrupting chemical (EDC), is a ubiquitous pollutant. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether exposure of Sprague-Dawley rats to 2,500 μg/kg/day BPA (BPA) or 0.5 μg/kg/day ethinyl estradiol (EE) from gestational day 6 through postnatal day 21 induces behavior-relevant gene expression and DNA methylation changes in hippocampus and hypothalamus at adulthood. RNA and DNA were isolated from both regions. Expression of ten genes (Dnmt1, Dnmt3a, Dnmt3b, Esr1, Esr2, Avp, Ar, Oxt, Otr, and Bdnf) presumably altered by early-life BPA/EE exposure was examined. Three genes (Bdnf, Dnmt3b, and Esr1) were studied for DNA methylation changes in their putative 5' promoter regions. Molecular changes in hippocampus were correlated to prior Barnes maze performance, including sniffing correct holes, distance traveled, and velocity. Exposure to BPA and/or EE disrupted patterns of sexually dimorphic gene expression/promoter DNA methylation observed in hippocampus and hypothalamus of controls. In the hippocampus of female offspring, BPA exposure resulted in hypermethylation of the putative 5' promoter region of Bdnf, while EE exposure induced hypomethylation. Bdnf methylation was weakly associated with Bdnf expression in hippocampi of female rats. Hippocampal Bdnf expression in females showed a weak negative association with sniffing correct hole in Barnes maze. Hippocampal expression of Avp, Esr2, Oxt, and Otr was strongly associated with velocity of control rats in Barnes maze. Findings suggest BPA exposure induced non-EE-like gene expression and epigenetic changes in adult rat hippocampi, a region involved in spatial navigation.
双酚 A（BPA），一种内分泌干扰化学物质（EDC），是一种普遍存在的污染物。作为连接学术和监管对 BPA 毒性的见解联盟（CLARITY-BPA）的一部分，我们试图确定从妊娠第 6 天到出生后第 21 天，暴露于 2500μg/kg/天 BPA（BPA）或 0.5μg/kg/天乙炔雌二醇（EE）的 Sprague-Dawley 大鼠是否会在成年期引起海马体和下丘脑与行为相关的基因表达和 DNA 甲基化变化。从这两个区域分离 RNA 和 DNA。检查了十个基因（Dnmt1、Dnmt3a、Dnmt3b、Esr1、Esr2、Avp、Ar、Oxt、Otr 和 Bdnf）的表达，这些基因的表达可能因早期 BPA/EE 暴露而改变。研究了三个基因（Bdnf、Dnmt3b 和 Esr1）在其假定的 5'启动子区域的 DNA 甲基化变化。海马体中的分子变化与之前的 Barnes 迷宫表现相关，包括嗅探正确的孔、行驶距离和速度。暴露于 BPA 和/或 EE 破坏了对照组海马体和下丘脑观察到的性别二态基因表达/启动子 DNA 甲基化模式。在雌性后代的海马体中，BPA 暴露导致 Bdnf 假定的 5'启动子区域的超甲基化，而 EE 暴露导致低甲基化。Bdnf 甲基化与雌性大鼠海马体中 Bdnf 表达呈弱相关。雌性大鼠海马体中的 Bdnf 表达与 Barnes 迷宫中嗅探正确孔呈弱负相关。Avp、Esr2、Oxt 和 Otr 在 Barnes 迷宫中控制大鼠的速度呈强烈相关。研究结果表明，BPA 暴露导致成年大鼠海马体中非 EE 样基因表达和表观遗传变化，海马体是参与空间导航的区域。
