双酚A胚胎期暴露对Th2和Treg细胞分化表观遗传调控的影响及其与0-3岁儿童哮喘的关系

It is indicated that prenatal exposure to bisphenol A (BPA) increases the susceptibility to asthma by animals studies. However, the mechanisms and the impact of prenatal exposure to BPA on the prevalence of asthma in human infants are not clear. We intend to base this study on both animal model and birth cohort. Firstly, we will establish the mouse prenatal BPA exposure model, and induce asthma with antigen stimuli in mouse, to study the influences of BPA exposure on Th2 and Treg cell differentiation in umbilical cord blood and the spleen. The methylation level and the methylation and acetylation states of histone H3 and H4 in Th2 locus (Il4-Il13-Rad50-Ill5) and FOXP3 gene, which regulate the Th2 and Treg cell differentiation, will be also studied. Then we will evaluate the level of prenatal BPA exposure in children in our birth cohort and detect the epigenetic changes of relative genes in the umbilical cord blood in asthma children, who will be identified by the follow-up study. Using matched nested case-control study, we will identify the relationship between prenatal BPA exposure and the prevalence of asthma in 0-3 year-old children. The mechanisms focused in the epigenetic changes of key genes which mediate the effects of BPA exposure will also be studied, which are helpful for elucidating the effect of prenatal exposure to BPA on the epigenetics. Finally, the impact of prenatal BPA exposure on the epigenetic control of Th2 and Treg cell differentiation and it's relationship with asthma in 0-3 year-old children will be elucidated. The results of this study will help us to understand the health effects of BPA exposure comprehensively, and also helpful for finding the the risk factors of infant asthma.

动物实验表明双酚A（bisphenol A, BPA）胚胎期暴露可增加哮喘风险，但其作用机制和对人群婴幼儿哮喘的影响尚不清楚。本项目拟首先建立小鼠BPA胚胎期暴露模型，抗原刺激诱发哮喘，研究BPA对脐血和脾Th2和Treg细胞分化的影响，及主要分化调控位点Th2位点（Il4-Il13-Rad50-Ill5）和FOXP3基因甲基化和组蛋白H3、H4甲基化和乙酰化状态改变；然后基于已建立的出生队列，随访确定哮喘病例，评估病例和对照胚胎期BPA暴露水平，检测脐血关键基因表观遗传改变，采用匹配巢式病例对照方法研究BPA胚胎期暴露与0-3岁儿童哮喘的关联，明确BPA对儿童哮喘风险的影响及作用规律，探讨关键基因表观遗传改变在其中的作用，最终阐明BPA胚胎期暴露对Th2和Treg细胞分化表观遗传调控的影响及其与0-3岁儿童哮喘的关系。本研究将为了解BPA的健康效应和婴幼儿哮喘的危险因素提供科学依据。

动物实验表明双酚A（bisphenol A, BPA）胚胎期暴露可增加哮喘风险，但其作用机制和对人群婴幼儿哮喘的影响尚不清楚。本项目首先建立了0，5，50 µg/kg.d BPA胚胎期暴露模型，小鼠出生后对其进行免疫诱导，发现胚胎期50 µg/kg.d BPA暴露可增加小鼠气道反应性，增加气道炎症因子分泌，脾脏Th2/Treg细胞平衡改变，且Th2位点甲基化水平下降，Treg细胞FOX3位点甲基化水平上升。进而，本项目利用出生队列人群研究了BPA，双酚S（BPS）和邻苯二甲酸酯（DEHP）类物质胚胎期暴露与婴幼儿哮喘和过敏性疾病的关系。结果显示， 1) 母亲孕晚期尿液BPA浓度与6个月婴儿过敏性疾病发生呈正相关，肌酐校正BPA浓度对数转换值（lnBPACS）每升高一个单位，过敏性疾病的发病率增加20%。2) 母亲孕晚期尿液MEHP浓度与6个月女婴过敏性疾病发生呈正相关，OR值为2.40(95% CI: 1.00-5.76)。3) 分析孕早、中和晚三期尿液BPA， BPS和DEHP浓度与2岁儿童湿疹与下呼吸道感染的相关性，发现胚胎期DEHP暴露增加儿童下呼吸道感染的发生风险，尿比重校正MEOHP浓度对数转换值（LnMEOHP）每升高一个单位，2岁儿童下呼吸道感染发病风险增加19% (RR, 1.19; 95% CI, 1.00-1.42; P =0.05)，LnMEHP(RR, 1.16; 95% CI, 1.02-1.32; P =0.02)和LnMNBP(RR, 1.26; 95% CI, 1.08-1.46; P =0.00)均与2岁儿童下呼吸道感染风险相关；BPA、BPS与儿童湿疹和下呼吸道感染均无明显相关性。4) 进一步分析暴露敏感期，发现孕早期BPA、BPS和DEHP浓度与儿童呼吸道感染和湿疹均无关联；孕中期MECPP、MEHHP、MEOHP、MIBP、MNBP浓度对数转换值每升高一个单位，下感风险分别增加17%、22%、23%、14%、30%，P<0.05；孕晚期尿液中MNBP对数转换值每升高一个单位，湿疹（RR, 1.14; 95% CI, 1.00-1.29）和下呼吸道感染（RR, 1.15; 95% CI, 1.03-1.13）风险均显著增加。5) 未发现母亲尿液BPA浓度与新生儿脐血淋巴细胞中Th2位点和FOX3位点甲基化水平的相关性。