GENETIC SUSCEPTIBILITY TO PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 多氯联苯（PCBs）是一种持久性有机污染物，可在食物链中生物累积，对健康造成许多不利影响，包括在子宫内和哺乳期接触的儿童的学习和记忆缺陷。首席研究员先前在小鼠中的研究发现了两个增加发育中PCB暴露易感性的基因  芳香烃受体（Ahr）和细胞色素P450 1A 2（Cyp 1a 2），一个由AHR直接调控的基因。 共面PCB与AHR结合，引发基因表达的变化。许多这些AHR调节基因参与中枢神经系统发育。AHR激活最近也被证明会影响DNA甲基化酶的活性。众所周知，糖皮质激素受体受差异甲基化的调节，受体水平的变化可以改变学习，记忆和对压力的反应。有趣的是，许多与AHR结合的污染物会改变应激激素水平或动物对应激的反应。该项目旨在验证AHR的持续激活通过表观遗传机制改变正常大脑发育和应激反应的假设。具体目标是： 1.）的人。比较皮质酮水平，焦虑和对压力的反应在多氯联苯处理和控制动物不同的AHR和Cyp 1a 2位点。 2.）的情况。确定发育PCB暴露是否改变海马体，皮质和下丘脑中基因特异性DNA甲基化模式。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Polychlorinated biphenyls (PCBs) are persistent organic pollutants that bio-accumulate in the food chain and cause a number of adverse health effects including learning and memory deficits in children exposed in utero and during lactation. The principal investigator's previous research in mice uncovered two genes that increase susceptibility to developmental PCB exposure  the aryl hydrocarbon receptor (Ahr) and cytochrome P450 1A2 (Cyp1a2), a gene directly regulated by the AHR. Coplanar PCBs bind to the AHR, triggering changes in gene expression. Many of these AHR-regulated genes are involved in central nervous system development. AHR activation was also recently shown to affect the activity of DNA methylases. The glucocorticoid receptor is well known to be regulated by differential methylation, and changes in receptor levels can alter learning, memory and the response to stress. Interestingly, many pollutants that bind to the AHR produce changes in stress hormone levels or an animal's response to stress. This project was designed to test the hypothesis that persistent activation of the AHR alters normal brain development and the response to stress via epigenetic mechanisms. The specific aims were to: 1.) Compare corticosterone levels, anxiety and response to stress in PCB-treated and control animals differing at the Ahr and Cyp1a2 loci. 2.) Determine if developmental PCB exposure alters gene-specific DNA methylation patterns in the hippocampus, cortex and hypothalamus.