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: 9186544
• 负责人: Pamela J Lein
• 金额: $ 51.5万
• 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 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186544
• 关键词: Address; Affect; Air; Apoptosis; Behavior; Biochemical; Biological; Birth; Blood; Brain; CGG repeat expansion; CREB1 gene; Calcium; Calcium/calmodulin-dependent protein kinase; Child; Child health care; Chlorine; Complex; Complex Mixtures; Data; Development; Diagnosis; Diet; Electrophysiology (science); Environment; Environmental Risk Factor; Etiology; Event; Exposure to; FMR1; FMR1 repeat expansion; Female; Food Contamination; Funding; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Growth; Heritability; Hippocampus (Brain); Hormone Responsive; Human; Impaired cognition; Industrialization; Knock-in; Knock-in Mouse; Lactation; Link; Liver; Longitudinal Studies; Mediating; Messenger RNA; Molecular; Mothers; Mus; Mutation; National Health and Nutrition Examination Survey; Nervous system structure; Neurodevelopmental Disorder; Neurodevelopmental Impairment; Neurons; Outcome; Oxidative Stress; Plasma; Polychlorinated Biphenyls; Predisposition; Pregnancy; Pregnant Women; Process; Production; Rattus; Reporting; Risk; RyR1; Ryanodine Receptor Calcium Release Channel; Sampling; Schools; Signal Pathway; Signal Transduction; Structure-Activity Relationship; Testing; Thyroid Hormone Receptor; Thyroid Hormones; United States; Vertebral column; Weaning; Woman; autism spectrum disorder; base; comparison group; congenic; critical period; developmental neurotoxicity; disorder risk; experience; gain of function mutation; gene environment interaction; gene interaction; indexing; knockin animal; mTOR Signaling Pathway; male; mouse model; neurodevelopment; neuron apoptosis; neurotoxicity; public health relevance; response; screening; synaptogenesis

DESCRIPTION (provided by applicant): Polychlorinated biphenyls (PCBs), and in particular neuroactive non-dioxin-like PCBs, remain a significant children's health concern because of their persistence and inadvertent production by various industrial processes that continue to contaminate food and indoor air, especially in schools across the United States. PCBs have been identified as probable environmental risk factors for neurodevelopmental disorders (NDD), which affect 1 in 10 children born in the United States. Most NDD have complex etiologies that likely involve multiple genetic loci interacting with exposures to environmental factors during critical periods of neurodevelopment. While many genes have been associated with increased risk of NDD, there remains a huge gap in understanding how multiple genes interact to modify neurodevelopment and even less clarity as to how genetic susceptibilities interact with environmental factors to amplify NDD risk. We will address these questions by testing the hypothesis that exposure during critical window(s) of neurodevelopment to a mixture of PCBs found in mothers at risk for having a child with NDD will potently disrupt neuronal connectivity via ryanodine receptor (RyR)-dependent mechanisms and the net outcome will be influenced by heritable mutations that alter the fidelity of Ca2+ signals essential for activity-dependent dendriic growth. This hypothesis derives from data generated during the previous funding cycle demonstrating sensitization of the ryanodine receptor (RyR) by PCB 95 activates calcium-dependent signaling pathways that promote dendritic arborization, and increased dendritic arborization is associated with impaired cognitive behavior in weanling mice exposed to PCB 95 in the maternal diet. The studies described in this application will use a PCB mixture that is relevant to human NDD based on data of PCB levels in the plasma of mothers participating in the MARBLES study at UC Davis, a longitudinal study for pregnant women with increased risk for having a child with NDD. This "MARBLES mix" will be tested for effects on morphometric, biochemical and functional indices of neuronal connectivity in unique mouse models that express an expansion repeat in the FMR1 gene, the single most frequent monogenetic cause of neurodevelopmental impairments, and a human RyR1 gain of function mutation, singly or in combination. These studies will address the critical need to better understand mechanisms by which non-dioxin-like PCBs cause developmental neurotoxicity, and will provide among the first mechanistic data regarding relevant interactions among genes and environment that increase NDD risk. This information will inform rational strategies for minimizing NDD risk by mitigating relevant exposures and will facilitate the development of mechanistically based screening platforms for identifying other gene-environment interactions likely to amplify adverse neurodevelopmental outcomes.

描述（由申请人提供）：多氯联苯，特别是神经活性的非二恶英样多氯联苯，仍然是儿童健康的重要问题，因为它们的持久性和无意中由各种工业过程产生，继续污染食品和室内空气，特别是在美国各地的学校。多氯联苯已被确定为神经发育障碍（NDD）的可能环境风险因素，在美国出生的儿童中有十分之一受其影响。大多数NDD具有复杂的病因，可能涉及多个遗传位点与神经发育关键时期暴露于环境因素的相互作用。虽然许多基因与NDD风险增加有关，但在了解多种基因如何相互作用以改变神经发育方面仍然存在巨大差距，而遗传易感性如何与环境因素相互作用以增加NDD风险则更不清楚。我们将通过测试假设来解决这些问题，即在神经发育的关键窗口暴露于有NDD儿童风险的母亲中发现的多氯联苯混合物会通过ryanodine受体（RyR）依赖机制潜在地破坏神经元连接，并且最终结果将受到遗传性突变的影响，这些突变会改变活性依赖性树突生长所必需的Ca2+信号的保真度。这一假设来源于上一个资助周期中产生的数据，该数据表明PCB 95对ryanodine受体（RyR）的致敏作用激活钙依赖性信号通路，促进树突生长，并且在母体饮食中暴露于PCB 95的断奶小鼠中，树突生长的增加与认知行为受损有关。本申请中描述的研究将使用与人类NDD相关的多氯联苯混合物，该混合物基于参与加州大学戴维斯分校MARBLES研究的母亲血浆中多氯联苯水平的数据，该研究是一项针对孕妇的纵向研究，其孩子患NDD的风险增加。这种“大理石混合物”将在独特的小鼠模型中进行测试，以检测其对神经元连接的形态计量学、生化和功能指标的影响，这些模型表达FMR1基因中的扩增重复序列，这是神经发育障碍的单一最常见的单基因原因，以及人类RyR1功能突变的获得，单独或组合。这些研究将解决更好地了解非二恶英样多氯联苯引起发育性神经毒性机制的关键需求，并将提供有关基因和环境之间相关相互作用增加NDD风险的第一批机制数据。这些信息将为通过减少相关暴露来最小化NDD风险的合理策略提供信息，并将促进基于机制的筛选平台的发展，以识别可能放大不良神经发育结果的其他基因-环境相互作用。