Molecular and Cellular Basis of PCB Developmental Neurotoxicity

描述（由申请人提供）：多氯联苯（PCB），特别是具有神经活性的非二恶英类PCB，仍然是儿童健康的一个重大问题，因为它们具有持久性，并且在各种工业过程中无意产生，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可能的环境风险因素，神经发育障碍（NDD），影响1在美国出生的10名儿童。大多数NDD有复杂的病因，可能涉及多个遗传基因座相互作用，在神经发育的关键时期暴露于环境因素。虽然许多基因与NDD风险增加有关，但在理解多个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，并且对于遗传易感性如何与环境因素相互作用以放大NDD风险的问题更不清楚。我们将通过检验以下假设来解决这些问题：在神经发育的关键窗口期间，暴露于在有NDD风险的母亲中发现的多氯联苯混合物中，将通过兰尼碱受体（RyR）依赖机制有力地破坏神经元连接，并且净结果将受到遗传突变的影响，这些突变改变了对活性依赖性树突生长至关重要的Ca 2+信号的保真度。这一假设来自上一个资助周期期间产生的数据，表明PCB 95对ryanodine受体（RyR）的致敏作用激活了促进树突状分支的钙依赖性信号通路，并且树突状分支的增加与暴露于母体饮食中PCB 95的断奶小鼠的认知行为受损相关。本申请中描述的研究将使用与人类NDD相关的PCB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PCB水平的数据，该研究是一项针对NDD儿童风险增加的孕妇的纵向研究。将在表达FMR 1基因中的扩增重复序列（神经发育障碍的单一最常见单基因原因）和人类RyR 1功能获得突变（单独或组合）的独特小鼠模型中，测试这种“大理石混合物”对神经元连接的形态测定、生物化学和功能指标的影响。这些研究将满足更好地了解非二恶英类多氯联苯引起发育神经毒性的机制的迫切需要，并将提供有关基因和环境之间增加NDD风险的相关相互作用的第一批机制数据。这些信息将为通过减轻相关暴露来最大限度地降低NDD风险的合理策略提供信息，并将促进基于机制的筛查平台的开发，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。

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.