交通污染对儿童自闭症发病的影响及表观遗传机制研究

The incidence of children autism has increased rapidly last five years, while etiology and mechanisms of autism are unclear. Traffic pollution is a major source of air pollution in city, which is related to children autism and has attracted increasing attention. With base on the environmental epigenetic platform established by previous research, the case-control study nested in a cohort is innovatively combined with experimental animal Experimental study of natural exposure to traffic pollution sit. The cases and controls all receive the epidemiological investigation of environment, and the epigenetic changes (whole genome DNA methylation, special gene methylation and histone methylation) in their blood are quantitatively tested. After Wistar exposed to various degree traffic pollution before and after birth, respectively, the many epigenetic changes are detected in the cerebrum and cerebellum tissue of Wistar offspring, respectively, and their relationship are analyzed. The results have declared the features and risk factors of children autism, and the traffic pollution result in risk of autism in children and is related to different epigenetic changes. It is first time that the epigenetic characteristics and its molecular mechanism related to autism are revealed in brain tissues after early life expose to traffic pollution. The purpose is to provide scientific basis for the creation of early risk assessment system and effective measures of prevention & treatment, understanding the pathogenesis of children autism.

儿童自闭症近五年发病人数增长迅猛且病因机制未明。交通污染作为城市空气污染的主要来源，与儿童自闭症的关系日益引起人们高度关注。本项目基于前期研究建立的环境表观遗传科研平台，创新地将巢式病例-对照研究与实验动物交通污染现场自然暴露实验研究相结合，对出生队列内自闭症患儿与正常对照进行环境流行病学追踪调查，定量检测患儿及正常对照血液中表观遗传变异水平（全基因组DNA、多个特定基因及组蛋白的异常甲基化），分析出生前后暴露于不同交通污染现场的Wistar仔鼠大、小脑组织中与自闭症相关表观遗传变异及相互关系。阐明儿童自闭症发病特征及影响因素、交通污染所致儿童自闭症风险大小及其与自闭症表观遗传变异的关系。首次揭示生命早期交通污染所致脑组织中与自闭症相关表观遗传变异特征及分子机制。为建立儿童自闭症发病风险的早期评价体系、制订有效防治措施、深入认识自闭症病因及发病机制，提供科学依据。

儿童自闭症近五年发病人数增长迅猛且病因机制未明。交通污染作为城市空气污染的主要来源，与儿童自闭症的关系日益引起人们高度关注。本项目创新地将巢式病例-对照研究与实验动物交通污染现场自然暴露实验研究相结合，对出生队列内316自闭症患儿与293正常对照进行环境流行病学追踪调查，同时收集了头发和指甲样本并对其进行了多个金属（铅、汞、砷、铜、镁、铝、锰、锌）含量检测。分析出生前后暴露于不同交通污染现场的Wistar仔鼠大、小脑组织中与自闭症相关表观遗传变异（全基因组DNA、多个特定基因及组蛋白的异常甲基化）及相互关系。研究结果表明:(1)母亲产前抑郁症、妊娠期高血压、儿童先天性心脏病、疫苗接种情况、母亲日常微波炉的使用、辛辣食物的摄入、孕早、中期和生后1年居住地到主干道距离近以及儿童体内铅、砷、锰、锌元素水平与自闭症发生有关；(2)表观遗传指标检测显示，胚胎期暴露于较高浓度交通污染会导致LINE-1基因平均甲基化水平显著下降（PEM<0.05, PEH<0.001）和OXTR基因平均甲基化水平增加（PEH<0.001），出生后暴露组则未发生显著改变；出生前后交通污染暴露并不会使组蛋白H3K4总甲基化及H3K4me3水平发生显著改变；出生后暴露组中LINE-1基因平均甲基化水平与H3K4总甲基化水平呈正相关（r=0.265，P=0.041），其他各指标无明显相关; (3)产后暴露的大鼠脑前额叶组织SHANK3基因启动子区域CpG岛甲基化水平升高，且部分CpG位点甲基化水平呈浓度依赖性升高。交通污染可导致早期大脑H3K27me3表达水平降低，且雄性更易受到影响。此外，出生后暴露的大鼠H3K27me3表达量更低。为建立儿童自闭症发病风险的早期评价体系、制订有效防治措施、深入认识自闭症病因及发病机制，提供科学依据。