Molecular and Cellular Basis of PCB Developmental Neurotoxicity

PCB 发育神经毒性的分子和细胞基础

• 批准号: 7991326
• 负责人: Pamela J Lein
• 金额: $ 46.82万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991326
• 关键词: Address; Animals; Aroclor 1254; Behavior; Behavioral; Bicuculline; Biological; Biological Markers; Brain; CREB1 gene; Calcium; Calcium/calmodulin-dependent protein kinase; Cells; Chemicals; Child; Coculture Techniques; Cognitive; Data; Dendrites; Dendritic Spines; Development; Diet; Dose; Environmental Health; Environmental Pollution; Event; Exhibits; Exposure to; Family; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; Growth; Hippocampus (Brain); Human; Image Analysis; In Vitro; Learning; Link; Lipid Bilayers; Location; Measurable; Mediating; Memory; Molecular; Molecular Target; Mus; Mutation; Nature; Nervous system structure; Neuraxis; Neurodevelopmental Disorder; Neuroglia; Neurons; Outcome; Parents; Pattern; Perinatal Exposure; Polychlorinated Biphenyls; Population; Predisposition; Proteins; Rattus; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Risk; Rodent; Role; RyR1; RyR2; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Screening procedure; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Structure-Activity Relationship; Synapses; Testing; Thyroid Hormones; Time; Training; Transgenic Mice; Validation; Western Blotting; base; cognitive function; density; developmental neurotoxicity; experience; gene environment interaction; human FRAP1 protein; in vivo; insight; morris water maze; neurodevelopment; neuronal cell body; neurotoxicity; novel; protein expression; receptor; reconstitution; research study; response; tool

DESCRIPTION (provided by applicant): 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. Polychlorinated biphenyls (PCBs) are persistent, widespread environmental contaminants, and there is compelling evidence that exposure of the developing brain to PCBs can cause learning and memory problems in children. But how PCBs cause these effects is not well understood. The goal of the proposed studies is to link known molecular effects of PCBs (activation of ryanodine receptors) to specific changes in brain development (disruption of dendritic growth). Establishing this link will provide a powerful means for predicting which of the 209 possible PCBs present the greatest risk to the developing brain and may provide novel insights into genetic susceptibilities that magnify environmentally induced neurodevelopmental disorders.

描述(由申请人提供)：公众和监管机构相当关注儿童发育过程中暴露于多氯联苯(PCbs)会导致严重的认知和行为缺陷，但评估这些化合物所构成的风险一直很困难，因为多氯联苯对发育中神经系统的影响的生物学机制尚未确定。我们最近证明，在发育过程中，啮齿动物暴露在商业多氯联苯混合物中会损害树突生长和体内的可塑性，这与空间学习障碍是一致的。这些对神经发育和认知功能的影响与中枢神经系统中兰尼定受体(RyR)表达和功能的改变有关。RyR调节钙依赖的信号通路，这些信号通路与活性依赖的树突状细胞生长有关，而树突状细胞生长是发育中大脑神经元连接的关键决定因素。本研究的目的是通过验证非共面多氯联苯通过破坏RyR功能改变树突状细胞生长和可塑性的假说来表征多氯联苯发育神经毒性的机制和构效关系(SAR)。其具体目标是：1.测试RyR扰动和甲状腺激素缺乏对体内多氯联苯的树突生长和可塑性的相对贡献；2.使用海马神经元的原代培养，以确定多氯联苯对树突生长影响的分子机制；3.确定非共面多氯联苯如何改变培养的海马神经元中组成钙释放单位的蛋白质的功能和表达；4.确定RyR1和ryr2的可遗传突变是否增加了表达这些突变的小鼠对多氯联苯发育神经毒性的敏感性。这些研究解决了更好地了解多氯联苯发育神经毒性潜在机制的迫切需要。结果将为确定暴露风险和开发暴露和影响的生物标记物提供合理的基础。由于RyR基因在人类群体中表现出大量的表达突变和多态，支持RyR作为发育中神经系统中多氯联苯的分子靶点的数据将为放大环境诱导的神经发育障碍的遗传易感性提供洞察力。多氯联苯是一种持久、广泛的环境污染物，有令人信服的证据表明，将发育中的大脑暴露于多氯联苯会导致儿童的学习和记忆问题。但多氯联苯是如何引起这些影响的还不是很清楚。这项拟议研究的目标是将已知的多氯联苯的分子效应(激活兰诺定受体)与大脑发育的特定变化(破坏树突生长)联系起来。建立这种联系将为预测209种可能的多氯联苯中哪些对发育中的大脑构成最大风险提供强有力的手段，并可能为放大环境诱导的神经发育障碍的遗传易感性提供新的见解。