【摘要】 目的 评估母亲围孕期室内空气污染暴露与后代神经管缺陷（neural tube defects, NTDs）发生风险的关联，并探索母亲胎盘脱氧核糖核酸（deoxyribonucleic acid,DNA）甲基化在其中的潜在作用。方法 基于2003—2016年在NTDs高发地区山西省开展的一项出生缺陷病例对照研究中的产妇信息，排除胎盘余量不足者后，按照产妇末次月经日期（last menstrual period,LMP）接近（±2周）的原则进行1∶1匹配，最终纳入128名NTDs儿的母亲作为病例组和128例健康新生儿母亲作为对照组。基于问卷信息，整合取暖、烹饪与吸烟来源，构建室内空气污染暴露评价指数（indoor air pollution exposure evaluation index,IAPEEI），并检测母亲胎盘组织DNA中与发育、代谢及应激相关基因（MTHFR、NR3C1、AHRR、CYP1A1和IGF2）CpG位点甲基化水平。使用条件logistic回归计算IAPEEI、DNA甲基化水平与NTDs发生风险的关联，使用多重线性回归计算IAPEEI和DNA甲基化水平的关联。结果 在调整混杂因素后，与无室内空气污染组相比，IAPEEI≥2组NTDs的发生风险为4.64倍（a OR=4.64, 95%CI:1.33～16.14），且呈显著剂量-反应关系（P趋势=0.001）。MTHFR基因CpG＿34位点甲基化升高显著增加NTDs发生风险（a OR=1.59, 95%CI:1.04～2.44）,AHRR基因CpG＿1位点、IGF2基因CpG＿8位点甲基化水平升高对NTDs具有保护效应（a OR=0.04, 95%CI:0.01～0.82和a OR=0.34, 95%CI:0.12～0.97）。同时，IAPEEI与CYP1A1基因CpG＿34位点、IGF2基因的CpG＿4位点、MTHFR基因的CpG＿30.31.32位点以及NR3C1基因的CpG＿10.11位点甲基化水平呈现显著负向关联。结论 围孕期母亲室内空气污染与胎盘DNA甲基化水平改变有关，可能通过降低胎盘IGF2等基因甲基化水平增加后代NTDs的发生风险。本研究为环境表观遗传机制提供人群层面的证据，提示NTDs高发地区应加强降低室内污染暴露的公共卫生干预。更多还原

【Abstract】 Objective To evaluate the association between maternal exposure to indoor air pollution during the periconceptional period and the risk of neural tube defects（NTDs） in offspring, and to explore the potential mechanistic role of placental deoxyribonucleic acid（DNA） methylation. Methods Data were utilized from a case-control study on birth defects conducted in Shanxi Province — a region with high NTD incidence — between 2003 and 2016. Maternal participants were selected according to the following criteria: exclusion of those with insufficient placental tissue, followed by 1∶1 matching based on proximity of last menstrual period（LMP） date（± 2 weeks）. The final sample comprised 128 mothers of infants with NTDs（case group） and 128 mothers of healthy newborns（control group）. Based on questionnaire data, sources of heating, cooking, and smoking were integrated to construct an indoor air pollution exposure evaluation index（IAPEEI）. DNA methylation levels at CpG sites of genes related to development, metabolism,and stress response（MTHFR, NR3C1, AHRR, CYP1A1, and IGF2） were quantified in maternal placental tissue DNA. Conditional logistic regression employed to estimate associations of IAPEEI and DNA methylation with NTD risk, while multiple linear regression was used to assess associations between IAPEEI and DNA methylation levels. Results After adjusting for confounding variables,participants with IAPEEI ≥ 2 demonstrated a 4.64-fold increased NTD risk compared to those with no indoor air pollution exposure（a OR = 4.64, 95% CI: 1.33 – 16.14）, with a significant dose-response relationship(Pt_rend = 0.001). Higher methylation at MTHFR CpG＿34 was associated with increased NTD risk（a OR = 1.59, 95% CI: 1.04 – 2.44）, whereas higher methylation at AHRR CpG＿1 and IGF2 CpG＿8 showed protective effects against NTDs（a OR = 0.04, 95% CI: 0.01 – 0.82 and a OR = 0.34, 95% CI: 0.12 – 0.97,respectively）. Additionally, IAPEEI demonstrated significant inverse associations with methylation levels at CYP1A1 CpG＿34, IGF2 CpG＿4, MTHFR CpG＿30.31.32, and NR3C1 CpG＿10.11. Conclusion Periconceptional maternal exposure to indoor air pollution is associated with altered placental DNA methylation and may increase offspring NTD risk through hypomethylation of critical genes such as IGF2. These findings provide population-level evidence for environmental epigenetic mechanisms and emphasize the urgent need for public health interventions to reduce indoor pollution exposure in NTDs high-incidence regions.更多还原