大气细颗粒物孕期暴露对子代神经发育影响及胎盘外泌体介导的免疫调控机制研究

Ambient fine particulate matter (PM2.5) pollution has become one of the major contributors to public health burden in China. As PM2.5 and its toxic constituents are able to cross the placental barrier, prenatal exposure to PM2.5 might affect fetal development and even be responsible for adult diseases. It's been shown that PM2.5 exposure during pregnancy was related to adverse birth outcomes in newborns and decreased respiratory function of offspring. However, it's still unclear whether prenatal PM2.5 exposure could disturb the neuro-development in children and need more human epidemiological evidences. Based on Shanghai Healthy Kids Cohort Study, we will assess maternal exposure levels of PM2.5 via individual PM2.5 exposure monitoring and satellite-based pm2.5 estimation in the current study. By using the survey data including children’s neurodevelopmental examination, maternal immune inflammatory factors and placenta function, we will evaluate the effect of prenatal exposure to PM2.5 on the neurodevelopment of offspring and its potential E-R curve. Furthermore, we will screen the epigenetic biomarkers in placental exosomes associated with PM2.5 exposure and components and investigate the involved epigenetic and immuno-regulation mechanism by the method of high-throughput omics analysis. Results are expected to get the population-based evidence and sensitive biomarkers of adverse effects of prenatal PM2.5 exposure in offspring. We wish these evidences will contribute to the control of atmospheric pollution and reduce childhood diseases burden in China.

大气细颗粒物（PM2.5）及其毒性组分可通过胎盘屏障，对子代生长发育及疾病状态产生长远影响。现有研究数据支持孕期PM2.5暴露对出生结局及子代呼吸功能的影响，但对于PM2.5对婴幼儿神经发育的影响尚缺乏人群流行病学证据支持。本研究基于上海亲子队列，拟在构建孕期PM2.5暴露模型和个体监测的基础上，综合评估孕期PM2.5的个体暴露水平，并结合子代神经发育状况随访、母体免疫炎症状态和胎盘功能检测，研究孕期大气PM2.5及其关键组分暴露对婴幼儿神经发育影响的暴露-反应关系及其免疫调控机制；在此基础上，运用高通量的组学分析方法筛选和验证胎盘外泌体中敏感的生物学标志物，进一步深入探索孕期PM2.5暴露对婴幼儿神经发育影响的表观遗传学机制。研究预期将获得我国PM2.5孕期暴露与子代健康效应的人群证据和敏感的生物标志物，为控制大气污染、降低儿童疾病负担做出贡献。

大气细颗粒物（PM2.5）及其毒性组分可通过胎盘屏障，对子代生长发育及疾病状态产生长远影响。现有研究数据支持孕期PM2.5暴露对出生结局及子代呼吸功能的影响，但对于PM2.5对婴幼儿神经发育的影响尚缺乏人群流行病学证据支持。. 本研究依托上海亲子队列，通过PM2.5精准暴露预测模型、个体采样监测和儿童神经发育评估，探索孕期PM2.5及其组分暴露对子代神经发育的影响。结果表明，孕期PM2.5暴露可增加婴幼儿多个神经发育能区的可疑发育迟缓的风险以及情绪和行为问题异常的风险；孕中晚期（孕18-35周）可能是PM2.5暴露影响婴幼儿神经发育的敏感窗口期。固定群组研究发现，孕期PM2.5荷载的Al、Ti、V和Pb金属组分暴露可能增加婴幼儿沟通、解决问题和个人-社会能区可疑发育迟缓风险，提示这些组分可能是PM2.5暴露影响子代神经发育的关键组分。. 进一步从胎盘免疫调控和胎盘外泌体miRNA介导的表观遗传学调控角度，探究了孕期PM2.5及其组分暴露影响子代神经发育潜在生物机制。研究发现，孕期PM2.5及关键组分暴露增加TNF-α、IL-6和IL-1β等炎症因子表达水平，并干扰胎盘外泌体miRNAs及其参与的调控生长发育、神经发育、发育编程、代谢疾病等生物学过程，胎盘外泌体miR-320a-3p是PM2.5影响神经发育的生物标志。因此，孕期PM2.5及其组分暴露可能通过干扰胎盘外泌体miRNA表达和胎盘炎症反应影响儿童神经发育。.综上，本项目通过多时间点和多水平随访的出生队列研究系统评估了孕期PM2.5及其组分暴露对子代神经发育的影响，识别、鉴定了PM2.5神经发育毒性效应的关键组分，并首次从胎盘外泌体来源miRNA角度探究了产前PM2.5及其组分暴露影响子代神经发育的生物机制。研究结果为阐明PM2.5神经发育毒性作用机制提供了新的研究证据。