多环芳烃诱发自发性早产的效应与机制以及叶酸的保护作用

The effects of polycyclic aromatic hydrocarbons (PAHs) exposure on pregnancy outcomes are concerned greatly with its exposure increasing in our country. Emerging evidence suggested that PAHs exposure may result in preterm births, inflammatory response may play an important role, while folic acid may have an anti-inflamatory effect and prevent against preterm births. We propose to conduct a pregnancy cohort study and nested case-control study, combined with rat experiment to examine the association of maternal PAHs exposure during pregnancy with spontaneous preterm birth(SPB), the role of inflamatory response and the preventive effect of folic acid on SPB. About 3000 pregnant women will be recruited before 20 weeks gestation in Beijing urban area (mainly ourdoor air pollution) and Shanxi rural area (mainly indoor air pollution), respectively. Information related to PAHs exposure during first and second trimester and folic acid use will be investigted, and women’s venous blood samples will be collected during the recruitment. The recruited women will be followed to verify the pregnancy outcomes. In each cohort, 120 women with spontaneous preterm births and 120 matched controls will be selected respectively (480 subjects in total) for measurement of serum PAHs, inflammatory cytokines, as well as related gene polymorphisms. The associations of PAHs exposure and folic acid use in cohort study and the level of various biomarkers in nested case control study with preterm birth with be analyzed. Rat models of PAHs exposure and folic acid intervention will be established to directly observe the effects of PAHs on SPB and the molecular mechanisms by which PAHs may result in SPB, as well as protective effect of folic acid against PAHs-induced SPB.

随着我国多环芳烃（PAHs）污染的加剧，其对妊娠结局的影响备受关注。有研究提示，PAHs可诱发早产，炎性反应可能是其重要机制。本研究采用孕期队列及队列内病例对照研究、结合大鼠模型揭示孕期PAHs暴露对自发性早产（SPB）的诱发效应、炎性反应在其中的作用及叶酸拮抗PAHs诱发SPB的效应。拟在北京市城区（室外大气污染为主）和山西农村地区（室内空气污染为主）各募集约3000名孕20周之前的妇女，收集孕早、中期PAHs暴露及叶酸服用相关信息，采集妇女静脉血保存，随访妇女妊娠结局。从两个队列中各选择SPB病例及配比对照120对（共480名），测定血清PAHs浓度、相关代谢酶基因多态性及炎性因子水平。分析队列人群PAHs暴露及叶酸服用情况及病例对照人群各标志物与SPB的关系。通过构建大鼠PAHs染毒及叶酸干预模型，直观验证PAHs诱发SPB的效应和分子机制，以及叶酸对PAHs诱发SPB的保护作用。

目的：研究孕期PAHs暴露对自发性早产（SPB）的诱发效应、炎性反应在其中的作用及叶酸拮抗PAHs诱发SPB的效应。.方法：以孕期队列、巢式病例对照研究、以及大鼠模型进行研究。北京队列纳入4200名城区孕妇，山西队列纳入了3200名农村孕妇。巢式病例对照研究中，北京人群纳入了82名早产病例和331名正常对照，测定了发样PAH含量、30多种金属和类金属浓度。山西人群纳入146名病例以及381名正常对照，测定了血清中炎症因子、20多种PAHs代谢酶基因多态性、金属和类金属浓度、某些新型有机污染物浓度；通过构建大鼠孕早期BaP暴露及叶酸干预模型，进一步观察了PAHs致大鼠发生SPB的效应及可能的作用机制，以及叶酸的保护作用。.结果：山西农村地区早产率及自发性早产率远高于北京城市地区人群；山西农村地区妇女叶酸可有效降低自发性早产发生风险，保护率达到30%以上；北京人群未发现服用叶酸对早产具有任何保护作用。病例对照研究显示，北京城区孕妇头发中16种PAHs与早产及SPB发生风险均无显著关联性；山西农村孕妇孕早期血清铜和锰浓度较高与山西农村地区SPB发生风险增加显著相关，存在剂量反应关系；代谢酶基因rs2758352（MnSOD）多态位点与锰对SPB的发生存在交互作用；血清IL-8炎性因子与山西农村地区SPB发生风险存在关联方向关联性。动物实验表明，苯并(a)芘（BaP）高浓度暴露可致大鼠流（早）产比例增加及胚胎发育速度减缓，叶酸干预在一定程度上是可以改善胚胎的发育状况；高剂量的BaP暴露能导致胎盘组织中的炎性因子含量的改变，使机体处于炎症状态；而叶酸干预可以有效抑制某些炎性因子的表达。.结论：研究结果初步支持孕期高浓度PAHs暴露可增加自发性早产发生的风险，炎性反应参与了PAHs诱发SPB的机制，叶酸可有效拮抗PAHs诱发SPB的效应。研究结果对于我国早产的预防将提供一定的参考价值。