GENETIC SUSCEPTIBILITY TO PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 多氯联苯(PCBS)是一种持久性有机污染物，可在食品供应中生物积累并抵抗环境退化。2008年9月，肯塔基州确定了许多受多氯联苯污染的鱼类仍然是人类健康问题的水道。最近，人们发现了新的人类接触来源，包括用于老房子和学校的木材处理和建筑材料。对污染最严重地点附近人群的研究发现，在怀孕和哺乳期间暴露在空气中的儿童会出现学习、记忆和行为异常。并不是所有受感染的人都会经历同样程度的不利健康影响，这表明遗传差异在确定谁是风险最高的人方面很重要。申请人之前使用了一种新的小鼠模型来鉴定在大脑发育过程中影响对多氯联苯暴露易感性的两个基因：芳烃受体(Ahr)和细胞色素P450 1A2(CYP1A2)。多氯联苯处理的小鼠具有高亲和力的AHR，并且缺乏CYP1A2，在空间和非空间学习和记忆测试中显示出缺陷，并且惊吓反应减弱。产前应激可以产生类似的行为表型，伴随着糖皮质激素受体和受DNA甲基化调节的相关基因的表达减少。最近发现AHR的激活可以增加DNA甲基酶的活性。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应激的反应。

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.