基于出生队列的孕期细颗粒物暴露与婴幼儿哮喘的暴露-反应关系及表观遗传机制研究

Both air pollution and infant asthma are important public health issues in China. Several previous studies have demonstrated that prenatal exposure to PM2.5 was associated with the risk of asthma in infants. However, such studies are very few, hence neither the dose-response relationships between prenatal exposure to PM2.5 and asthma nor their biological mechanisms are very clear. Based existed findings, we hypothesize that prenatal exposure to PM2.5 during the sensitive pregnant periods could increase the risk of asthma in infants. The biological mechanisms may be that PM2.5 can interfere the methylation levels of FOXP3 and STAT6 genes in fetuses, which could further lead to unbalance of Th2/Treg cells, increase differentiation of Th2 cells, and finally trigger the onset of asthma in infants. In this study which is based on our established birth cohort in Guangzhou (the database and biobank have been established), we will employ a spatial statistical modeling to precisely assess maternal individual level exposure to PM2.5 in every week, test the methylation levels of FOXP3 and STAT6 genes in cord blood of neonates, follow these neonates to their three years old, and collect information of whether they will get asthma. We aim to verify the dose-response relationships between prenatal exposure to PM2.5 and asthma incidences in infants, confirm the possible sensitive exposure windows, and explore the epigenetic mechanisms under their relationships. These findings could provide solid evidence for the governments to update the air quality standards, and for the clinicians to take actions to reduce impact of air pollution on infant asthma in the future.

大气污染和婴幼儿哮喘均为我国重要的公共卫生问题。现有研究发现孕期PM2.5暴露与婴幼儿哮喘存在相关，然而，目前由于研究较少，二者之间的暴露-反应关系仍不明确，且其生物学机制也不清楚。基于前期研究，我们假设：孕妇在敏感孕期暴露于高浓度的PM2.5可增加婴幼儿哮喘的风险，生物学机制为PM2.5干扰胎儿FOXP3和STAT6基因的甲基化，导致Th2/Treg细胞失衡和Th2细胞分化增加，最终引发哮喘。本研究基于我们在广州建立的出生队列（已建立数据库和生物样本库），采用时空分布模型精确评估孕妇每个孕周PM2.5个体化暴露水平，检测新生儿FOXP3和STAT6基因甲基化水平，并随访其发生哮喘的情况至三岁，从而阐明孕期PM2.5与婴幼儿哮喘之间的暴露-反应关系，明确暴露敏感期，并揭示其表观遗传机制。结果可为政府修订空气质量标准提供科学依据，也可为临床采取预防和治疗措施降低婴幼儿哮喘的发病率提供参考

生命早期，包含胚胎期、胎儿期与婴幼儿期，是生长发育的关键时期，也是儿童肺功能发育的关键时期。婴幼儿喘息和哮喘是婴幼儿的一种常见的慢性疾病。据调查，全球有高达14%的儿童出现喘息和哮喘症状。我国大气污染引起的疾病负担尤为严重，其中PM2.5污染是主要原因。有越来越多的证据表明空气污染与婴幼儿喘息和哮喘之间存在关联，有研究调查了生命早期PM2.5暴露与婴幼儿喘息和哮喘之间的关联，但尚未能得出一致的结论，易感暴露窗口在很大程度上仍是未知的，且一些孕妇的特征是否对两者的关系有修饰效应仍然尚不明确。有研究提示新生儿DNA甲基化可能是喘息和哮喘发生的重要环节。据此，本研究在广州开展队列研究，旨在明确孕期空气粒径颗粒污染物暴露和PM2.5成分暴露与新生儿喘息和哮喘的关系，并探讨DNA甲基化在孕期大气颗粒污染物浓度暴露引起喘息和哮喘中的作用机制。研究发现在婴幼儿生命早期接触高水平的PM2.5暴露可能会增加婴幼儿喘息和哮喘的风险，关键的易感接触窗口可能包括假腺期、小管期和2岁前。同时，孕期大气颗粒污染物暴露对新生儿脐带血STAT6甲基化水平与婴幼儿哮喘或喘息呈正相关，而新生儿脐带血FOXP3甲基化水平与婴幼儿哮喘或喘息呈负相关。综上，本研究进一步明确了大气颗粒污染物及不同成分对喘息和哮喘的影响，并明确了暴露敏感期，DNA甲基化改变可能是在孕期大气颗粒污染物浓度暴露引起喘息和哮喘的重要机制。

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