Molecular and Cellular Basis of PCB Developmental Neurotoxicity

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，这种疾病在美国出生的儿童中每10人中就有1人受到影响。大多数NDD具有复杂的病因，可能涉及多个遗传位点，在神经发育的关键时期与环境因素相互作用。本申请中描述的研究将使用与人类新城疫相关的多氯联苯混合物，基于参与加州大学戴维斯分校大理石研究的母亲血浆中多氯联苯水平的数据，该研究是一项针对患有新城疫孩子风险增加的孕妇的纵向研究。这种“大理石混合物”将在独特的小鼠模型中测试对神经元连接的形态、生化和功能指标的影响，这些模型表达FMR1基因的扩展重复，FMR1基因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，单独或联合表达。

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.