Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Toxicol Lett. 2013 Feb 13;217(1):75-81. doi: 10.1016/j.toxlet.2012.12.004. Epub 2012 Dec 15.
Developmental exposure to lead (Pb) has adverse effects on cognitive functioning and behavior that can persist into adulthood. Exposures that occur during fetal or early life periods may produce changes in brain related to physiological re-programming from an epigenetic influence such as altered DNA methylation status. Since DNA methylation is regulated by DNA methyltransferases and methyl cytosine-binding proteins, this study assessed the extent to which developmental Pb exposure might affect expression of these proteins in the hippocampus. Long Evans dams were fed chow with or without added Pb acetate (0, 150, 375, 750 ppm) prior to breeding and remained on the same diet through weaning (perinatal exposure group). Other animals were exposed to the same doses of Pb but exposure started on postnatal day 1 and continued through weaning (early postnatal exposure group). All animals were euthanized on day 55 and hippocampi were removed. Western blot analyses showed significant effects of Pb exposure on DNMT1, DNMT3a, and MeCP2 expression, with effects often seen at the lowest level of exposure and modified by sex and developmental window of Pb exposure. These data suggest potential epigenetic effects of developmental Pb exposure on DNA methylation mediated at least in part through dysregulation of methyltransferases.
发育过程中接触铅 (Pb) 会对认知功能和行为产生不良影响，并可能持续到成年期。胎儿期或生命早期的暴露可能会导致与生理重编程相关的大脑变化，这种变化受表观遗传影响，例如 DNA 甲基化状态的改变。由于 DNA 甲基化受 DNA 甲基转移酶和甲基胞嘧啶结合蛋白的调节，本研究评估了发育过程中 Pb 暴露在多大程度上可能影响海马体中这些蛋白质的表达。在繁殖前，长爪沙鼠母鼠食用添加或不添加醋酸铅 (0、150、375、750ppm) 的标准食物，并在哺乳期继续食用相同的饮食（围产期暴露组）。其他动物暴露于相同剂量的 Pb，但暴露从出生后第 1 天开始，并持续到哺乳期（早期产后暴露组）。所有动物在第 55 天被安乐死，取出海马体。Western blot 分析显示 Pb 暴露对 DNMT1、DNMT3a 和 MeCP2 表达有显著影响，在最低暴露水平下通常会出现影响，并且受到性别和 Pb 暴露的发育窗口的修饰。这些数据表明，发育过程中 Pb 暴露对 DNA 甲基化具有潜在的表观遗传效应，至少部分是通过甲基转移酶的失调介导的。
