Genetic Susceptibility to PCB-induced Motor Dysfunction

描述(申请人提供)：多氯联苯(PCB)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。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、记忆和运动障碍。动物研究表明，多氯联苯显著改变了大脑中的多巴胺浓度，这种毒性可能是通过兰诺定受体介导的。最近的证据表明，接触多氯联苯可能会增加患帕金森氏症的风险；[然而，多氯联苯对小脑的发育和功能也有重大影响。]并不是所有受感染的人都会经历同样程度的不良健康影响，这表明遗传差异会影响风险。我们之前在小鼠身上的研究发现了两个影响对多氯联苯引起的发育神经毒性易感性的基因：芳香烃受体(AHR)和细胞色素P450 1A2(CYP1A2)。具有高亲和力AHR且缺乏CYP1A2的AhrbCyp1a2(-/-)小鼠在发育过程中暴露于多氯联苯后表现出空间和非空间学习记忆障碍，而AhrbCyp1a2(/)小鼠具有抵抗力。我们(已公布的和新的)初步数据显示，运动障碍和学习和记忆障碍因性别和基因而异，使用对ryanodine受体几乎或根本没有活性的同系物的混合物。因此，我们假设，除了兰尼定受体介导的毒性外，[其他途径也参与了多氯联苯的发育神经毒性。为了验证这一假设，我们将使用这三个品系的小鼠来：1)比较接触多氯联苯的子代和用玉米油处理的对照组的运动功能。评估与运动功能相关的通路中的基因表达变化和串扰。3.)量化大脑区域中对正常运动功能至关重要的蛋白质水平。]

DESCRIPTION (provided by applicant): Polychlorinated biphenyls (PCBs) are persistent organic pollutants that bio-accumulate in the food supply and resist environmental degradation. Studies of human populations near the most polluted sites have found learning, memory and motor impairments in children exposed during pregnancy and breast-feeding. Animal studies show that PCBs significantly alter dopamine concentrations in the brain and that toxicity may be mediated through the ryanodine receptor. Recent evidence suggests PCB exposures may increase the risk of Parkinson's Disease; [however, PCBs also have significant effects on cerebellar development and function.] Not all exposed individuals experience the same level of adverse health effects, indicating that genetic differences affect risk. Our previous studies in mice identified two genes that affect susceptibility to PCB-induced developmental neurotoxicity: the aryl hydrocarbon receptor (AHR) and cytochrome P450 1A2 (CYP1A2). AhrbCyp1a2(-/-) mice with a high-affinity AHR and lacking CYP1A2 showed deficits in spatial and non-spatial learning and memory following developmental PCB exposure while AhrbCyp1a2(+/+) mice were resistant. Our [published and new] preliminary data show motor deficits and [learning and memory deficits that vary by sex and genotype using a mixture of congeners with little to no activity toward the ryanodine receptor. Therefore, we hypothesize that [additional pathways contribute to PCB developmental neurotoxicity in addition to toxicity mediated by the ryanodine receptor. To test this hypothesis, we will use these three lines of mice to: 1.) Compare motor function in PCB-exposed offspring and corn oil-treated controls 2.) Assess gene expression changes and crosstalk in pathways associated with motor function. 3.) Quantify protein levels in brain regions essential to normal motor function.]