GENETIC SUSCEPTIBILITY TO PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 多氯联苯（PCBs）是一种持久性有机污染物（POP），可在食品供应中生物积累，并抵抗环境降解。2008年9月，肯塔基州发现，在许多水道中，受多氯联苯污染的鱼类仍然是人类健康问题。最近，新的人类接触源已被确定，包括木材处理和旧住宅和学校使用的建筑材料。对污染最严重地区附近人群的研究发现，在怀孕和哺乳期间接触的儿童学习、记忆和行为异常。并非所有接触者都会经历相同程度的不良健康影响，这表明遗传差异在确定谁处于最高风险方面很重要。申请人先前使用了一种新的小鼠模型来鉴定影响大脑发育期间对PCB暴露的易感性的两种基因：芳香烃受体（Ahr）和细胞色素P450 1A2（Cyp1a2）。高亲和力AHR和缺乏CYP1A2的PCB处理小鼠在空间和非空间学习和记忆测试中表现出缺陷，惊吓反应减弱。产前应激可产生类似的行为表型，同时糖皮质激素受体和受DNA甲基化调控的相关基因表达减少。AHR激活最近被证明可以增加DNA甲基化酶的活性。因此，我们假设AHR的持续激活通过表观遗传机制改变了正常的大脑发育和对压力的反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that bio-accumulate in the food supply and resist environmental degradation. In September 2008, Kentucky identified numerous waterways where PCB-contaminated fish remain a human health concern. Recently, new sources of human exposure have been identified including wood treatments and construction materials used in older homes and schools. Studies of human populations near the most polluted sites have found learning, memory and behavioral abnormalities in children exposed during pregnancy and breast-feeding. Not all exposed individuals experience the same level of adverse health effects, indicating that genetic differences are important in determining who is at highest risk. The applicant previously used a novel mouse model to identify two genes which affect susceptibility to PCB exposure during brain development: the aryl hydrocarbon receptor (Ahr) and cytochrome P450 1A2 (Cyp1a2). PCB-treated mice with a high-affinity AHR and lacking CYP1A2 showed deficits in tests of spatial and non-spatial learning and memory and an attenuated startle response. Prenatal stress can produce a similar behavioral phenotype in conjunction with reduced expression of the glucocorticoid receptor and related genes regulated by DNA methylation. AHR activation was recently shown to increase the activity of DNA methylases. Therefore, we hypothesize that persistent activation of the AHR alters normal brain development and the response to stress via epigenetic mechanisms.