生命早期全氟化学物暴露影响儿童疫苗接种免疫应答的机制

Perfluoroalkyl substances are one of the persistent organic pollutants which can be widely detected in the environmental as well as humans. Immunotoxic effects of PFASs exposure have been found. However, the mechanism is still uncovered. Our previous study has preliminarily suggested the adverse association between prenatal exposure of PFASs and some vaccine responses, with more significant correlation in PFASs isomer exposure. Therefore, this project aims to investigate the mechanism involves in the vaccine antibody responses to prenatal exposure of PFASs in children from the established birth cohort study. Molecular epidemiological approaches are applied to investigate the immune balance in peripheral blood mononuclear cell and exposure fingerprint of PFASs in children. In combine with animal immune response model, DNA microarray and genomic DNA methylation profiles are employed to explore the feasibility of the variation of epigenetic patterns as novel biomarkers to predict the PFASs exposure and immune response. Bayesian network model is applied to analyze the correlation between prenatal PFASs exposure and the biological effects. Our goals devote to screening the key targets in the vaccine immune response to PFASs by analysis of dose-response relationship, investigating the mechanism involved in the immune response, and laying the foundation for health risk assessment in children to the PFASs exposure.

全氟化合物（PFASs）是一类在环境和人体中广泛存在的新型有机污染物，已有研究证实它具有免疫毒性，但毒性机制不明确。申请人课题组在前期建立的出生队列研究中发现脐带血典型PFASs的暴露与新生儿某些疫苗抗体水平呈负相关，异构体的效应比直链更为显著。因此，本项目在已建立的出生队列基础上，以人群暴露-动物模型-风险评估为主线，探讨生命早期PFASs暴露对儿童疫苗免疫应答的影响及机制。开展分子流行病学研究检测儿童外周血淋巴细胞免疫平衡，表征PFASs内暴露谱，结合疫苗免疫动物模型，利用转录组测序和基因组DNA甲基化谱筛查特异、可调控的表观遗传生物学标志。应用贝叶斯网络模型建立暴露与生物标志物的相关关系，通过剂量—反应关系分析筛查疫苗免疫应答的关键靶点，为探讨PFASs的免疫调控机制，开展儿童PFASs暴露的健康风险评估提供科学依据。

全氟化合物PFAS是一类在环境和人体中广泛存在的新型有机污染物，已有研究证实它具有免疫毒性，但其早期暴露的健康效应还有待进一步研究。本项目在团队前期建立的出生队列基础上，进一步构建了血清32种PFAS的检测方法，充分解析了孕期和脐带血中PFAS的暴露谱，系统地评估了PFAS的母婴暴露传递规律。研究结果发现新兴PFAS替代品的胎盘转运效率高于传统PFAS，通过分子流行病学的研究发现某些关键胎盘内运蛋白可能介导了PFAS及新兴替代品的胎盘转运效率。此外，课题组率先报导了孕期PFOS替代品（F-53B）的暴露与不良出生结局密切关联；阐述了孕期PFAS及替代品暴露对不良出生结局以及疫苗抗体水平的影响，发现PFAS暴露降低了儿童出生体重和疫苗抗体的水平；并通过乙肝疫苗接种小鼠模型评价PFAS暴露对乙肝疫苗接种小鼠CD4+ T细胞亚型和肝抗氧化酶的影响。研究结果以项目第一资助标注发表了6篇SCI文章，研究结果为进一步深入开展PFAS的敏感人群暴露风险评估提供了人群监测数据和理论依据。