Molecular and Cellular Basis of PCB Developmental Neurotoxicity

项目摘要 公众和监管机构都非常关注， 联苯（PCB）会导致儿童严重的认知和行为缺陷，但评估其风险 这些化合物一直是困难的，因为生物机制的PCB影响， 发育中的神经系统还有待鉴定。我们最近证明， 啮齿动物暴露于商业PCB混合物损害树突状细胞的生长和可塑性， 空间学习的缺陷。这些对神经发育和认知功能的影响与改变 中枢神经系统内兰尼碱受体（RyR）的表达和功能。RyR调节 钙依赖性信号传导通路与活性依赖性树突状细胞生长有关， 是发育中大脑神经元连接的关键决定因素。我们研究的目的是 通过以下方式描述PCB发育神经毒性的机制和构效关系（SAR）： 测试非共面PCB通过破坏RyR功能改变树突生长和可塑性的假设。 具体目标是： 1.测试RyR扰动和甲状腺激素缺乏在PCB影响中的相对贡献， 体内树突生长和可塑性; 2.利用原代培养的海马神经元鉴定介导PCB的分子机制 影响枝晶生长; 3.确定非共面PCB如何改变蛋白质的功能和表达， 培养海马神经元钙释放单位; 4.确定ryr 1和ryr 2中增加对卤化敏感性的遗传突变是否 化合物在人群中增加对PCB发育神经毒性的敏感性， 表达这些突变的小鼠。 这些研究解决了更好地了解PCB发展的潜在机制的迫切需要。 神经毒性结果将为描述暴露风险和开发生物标志物提供合理的基础 曝光和效果。由于RyR基因表现出显著数量的表达突变， 在人类群体中的多态性，数据支持RyR作为多氯联苯在发展中国家的分子靶点。 神经系统将提供对放大环境诱导的遗传易感性的见解 神经发育障碍

Project Summary There is considerable public and regulatory concern that developmental exposures to polychlorinated biphenyls (PCBs) cause significant cognitive and behavioral deficits in children, but assessing the risks posed by these compounds has been difficult because the biological mechanisms underlying PCB effects on the developing nervous system have yet to be identified. We have recently demonstrated that developmental exposure of rodents to a commercial PCB mixture impairs dendritic growth and plasticity in vivo coincident with deficits in spatial learning. These effects on neurodevelopment and cognitive function correlate with altered expression and function of ryanodine receptors (RyR) within the central nervous system. RyR regulate calcium-dependent signaling pathways that have been implicated in activity-dependent dendritic growth, which is a critical determinant of neuronal connectivity in the developing brain. The goal of our study is to characterize the mechanisms and structure-activity relationship (SAR) of PCB developmental neurotoxicity by testing the hypothesis that non-coplanar PCBs alter dendritic growth and plasticity by disrupting RyR function. The specific aims are to: 1. Test the relative contributions of RyR perturbation and thyroid hormone deficits in PCB effects on dendritic growth and plasticity in vivo; 2. Use primary cultures of hippocampal neurons to identify the molecular mechanisms mediating PCB effects on dendritic growth; 3. Determine how non-coplanar PCBs alter the function and expression of proteins that comprise calcium release units in cultured hippocampal neurons; 4. Determine whether heritable mutations in ryr1 and ryr2 that increase sensitivity to halogenated compounds in the human population increase susceptibility to PCB developmental neurotoxicity in mice expressing these mutations. These studies address the critical need to better understand mechanisms underlying PCB developmental neurotoxicity. Results will provide a rational basis for characterizing exposure risks and developing biomarkers of exposure and effect. Since RyR genes exhibit a significant number of expressed mutations and polymorphisms in the human population, data supporting RyR as a molecular target of PCBs in the developing nervous system will provide insights into genetic susceptibilities that magnify environmentally induced neurodevelopmental disorders.