Epigenetic Interaction of MECP2 and Organic Pollutants in Neurodevelopment

描述（由申请人提供）： 表观遗传机制作用于遗传学和环境之间的界面，是癌症或自闭症等复杂人类疾病风险的重要决定因素。该提案采用了各种系统和方法，重点关注持久性环境污染物对神经发育障碍中发生的精确表观遗传变化的影响这一核心问题。环境中多氯联苯和多溴联苯醚等持久性有机污染物的普遍存在及其在母乳中的检测结果引发了人们对子宫内和婴儿早期接触这些化合物的担忧。围产期暴露于多氯联苯和多溴二苯醚的大鼠在学习，记忆，行为和癫痫发作的易感性在成年期的长期缺陷。由于多氯联苯和多溴二苯醚的暴露，基因组的表观遗传变化以前没有被探索过，但这是对神经心理功能长期影响的一个合理解释。该提案将特别侧重于两种化合物，PCB 95和PBDE 47，这两种化合物在人类体内的含量很高，已知对神经发育有影响。拟议研究的遗传控制部分将使用Rett综合征和自闭症的基因工程Mecp2突变小鼠模型。除了动物研究之外，还将对来自自闭症、精神发育迟滞和对照个体的人类血液和死后大脑样本进行测试，以确定三个神经发育重要基因（MECP2、GABRB3、UBE3A）的精确表观遗传变化。由于将确定这些人体样本中的PCB和PBDE水平，因此可以进行暴露与表观遗传变化的相关性。这些研究将解决几个与公共卫生有关的问题：持久性有机污染物暴露会导致对神经发育有重要意义的基因发生哪些具体的表观遗传变化？在自闭症和精神发育迟滞的病因学中，已知的遗传和环境因素的复合效应是什么？特定的表观遗传学改变可以诊断自闭症和未知遗传病因的精神发育迟滞吗？影响神经发育的表观遗传变化是可遗传的吗？

DESCRIPTION (provided by applicant): Epigenetic mechanisms act at the interface between genetics and environment and are an important determinant in disease risk to complex human diseases such as cancer or autism. This proposal employs a combination of systems and approaches that focus on the central question of the impact of persistent environmental pollutants (POPs) on precise epigenetic changes that occur in neurodevelopmental disorders. The widespread prevalence of POPs such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in the environment and their detection in human milk has prompted concern about in utero and early infant exposure to these compounds. Perinatal exposure to PCBs and PBDEs in rats results in long-lasting defects in learning, memory, behavior, and seizure susceptibility in adulthood. Epigenetic changes to the genome as a result of PCB and PBDE exposures have not been previously explored but are a plausible explanation for the long-lasting effects on neuropsychological function. This proposal will focus specifically on two compounds, PCB 95 and PBDE 47, with high levels in humans and known effects on neurodevelopment. The genetically controlled component of the proposed studies will be to use a genetically engineered Mecp2 mutant mouse model of Rett syndrome and autism. In additional to animal studies, human blood and post-mortem brain samples from individuals with autism, mental retardation, and controls will be tested for precise epigenetic changes in three neurodevelopmentally important genes (MECP2, GABRB3, UBE3A). Since PCB and PBDE levels will be determined in these human samples, correlations of exposures to epigenetic changes can be performed. Several public health relevant questions will be addressed by these studies: What specific epigenetic changes to neurodevelopmentally important genes occur as a result of POP exposure? What is the compounding effect of known genetic and environmental factors in the etiology of autism and mental retardation? Can specific epigenetic changes be diagnostic for autism and mental retardation of unknown genetic etiology? Are epigenetic changes affecting neurodevelopment heritable?