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: 8197470
• 负责人: Pamela J Lein
• 金额: $ 45.89万
• 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/8197470
• 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

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.

项目摘要 有相当大的公众和监管机构关注发育过程中暴露在多氯化环境中 联苯(PCB)会导致儿童严重的认知和行为缺陷，但评估构成的风险 通过这些化合物一直很难，因为潜在的多氯联苯影响的生物机制 发育中的神经系统尚未确定。我们最近已经证明了发展 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可塑性，这与 在空间学习方面的缺陷。这些对神经发育和认知功能的影响与改变有关 兰尼定受体(RyR)在中枢神经系统中的表达和功能。RyR调节 参与活性依赖树突状细胞生长的钙依赖信号通路 是发育中大脑神经元连接的关键决定因素。我们研究的目标是 多氯联苯发育神经毒性机制及构效关系的研究 测试非共面多氯联苯通过破坏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扰动和多氯联苯中甲状腺激素缺陷对 体内树枝状生长和可塑性； 2.利用原代培养的海马神经元鉴定多氯联苯的分子机制 对枝晶生长的影响； 3.确定非共面多氯联苯如何改变包括以下内容的蛋白质的功能和表达 培养的海马神经元钙释放单位； 4.确定RyR1和ryr2的可遗传突变是否会增加对卤素的敏感性 人类种群中的化合物增加了对多氯联苯发育性神经毒性的敏感性 表达这些突变的小鼠。 这些研究解决了更好地了解多氯联苯发展的潜在机制的迫切需要 神经毒性。研究结果将为确定暴露风险和开发生物标志物提供合理的基础。 曝光率和效果。由于RyR基因表现出大量的表达突变和 人类群体中的多态现象，数据支持RyR作为发育中多氯联苯的分子靶标 神经系统将提供对放大环境诱导的遗传易感性的洞察 神经发育障碍。