多环芳烃复合暴露致胎儿神经管缺陷的协同效应及毒性机制研究

人群研究表明围孕期多环芳烃（PAH）暴露与胎儿神经管缺陷(NTD)发生风险增加有关。小鼠研究发现高剂量苯并[a]芘（BaP）可致胎鼠NTD的发生。近期研究发现，某些PAH，如荧蒽(FLT)可抑制细胞色素P450-1A(CYP1A)活性，同时显著增加BaP的致畸效应。环境中PAH常复合存在，但鲜见PAH复合暴露致NTD的研究。本课题以小鼠实验研究不同剂量Bap单独及与FLT联合暴露致NTD的效应及对CYP1A的影响。以非靶向代谢组学技术筛查小鼠血清中与PAH致NTD有关的内源性代谢物。小鼠实验的结果进一步在高发区人群病例对照研究中验证。于孕早、中期募集B超筛查诊断的NTD患儿及与之匹配的正常胎儿（130对），随访确认结局。采集妇女发样测定BaP、FLT母体及羟基代谢物评价PAH暴露和代谢状况，采集静脉血进行靶向代谢组学分析。综合小鼠和人群研究结果，确定PAH复合暴露致NTD的效应和机制。

Epidemiological studies suggested that periconceptioanal exposure to polycyclic aromatic hydrocarbons (PAH) may increase the risk of fetal neural tube defects (NTD). Mice experiments also suggested high doses of benzo[a]pyrene (BaP) could induce fetal NTD. Recent evidence suggested that some PAH, such as fluoranthene (FLT) can inhibit cytochrome P450-1A (CYP1A) activity, and meanwhile significantly increase the teratogenic effect of BaP. PAH in environment often exist in complex form. However, little is reported about the effect of combined PAH exposure on NTD. We propose to conduct the mice experiment to examine the effects of Bap exposure alone (in different doses) or joint exposure with FLT on the NTD occurrence in fetal mice, as well as the influence on CYP1A. Non-targeted metabolomics approaches will be used to extensively screen the endogenous metabolites in mice surum associated with the PAH induced NTD. The findings from mice experiment will be further verified by the case control study in high NTD prevelence areas. The NTD cases and one matched control (130 pairs) will be recruited at the time of type-B ultrasound scanning during earlier pregnancy, and will be followed to confirm the pregnancy outcome at delivery. Women’s hair samples will be collected in the recruitment, and hair BaP, FLT and their hydroxylated compounds will be measured for the assessment of PAH exposure and metabolism. Blood will be sampled for targeted metabolomics analysis to verify the discriminating metabolites identified from mice model. The effect of combined PAH exposure on NTD and potential mechanisms will be confirmed by combining the results from mice and human studies.