福州地区大气PM2.5及其主要毒性成分多环芳烃出生前暴露对胎儿心血管发育的不良效应

Fetus is regarded as one of the most vulnerable subjects, and cardiovascular system as one of the most susceptible systems with regard to airborne fine particulate matter (PM2.5) exposure. It is, therefore, extraordinarily necessary to understand the potential toxic effects of exposure to high or cirteria levels of PM2.5 or its major venenous components, on fetal cardiovascular system. However, there have been rare experimental research reports on this issue. In the present applying project, samples of the local PM2.5 and its derivative polycylic aromatic hydrocarbons (PAHs) will be prepared with their major toxic components analyzed. The effects of prenatal exposure to high levels or criteria levels of PM2.5, or its major toxic conponent PAHs, on fetal cardiovascular development will be experimentally investigated in murine exposure models via intratracheal instillation of the resuspended PM2.5 or resolved PAHs, or via inhalation of local PM2.5 at the ambient levels. The mechanisms by which prenatal PM2.5 or PAHs exposure acts on fetal cardiovascular system will be explored. In the clinical study, the sensitive indicators for fetal cardiavascular development in relation to prenatal exposure to PM2.5 will be investigated in the fetuses with different subtypes of congenital heart diseases to further prove the results from the experimental studies and to uncover the underlying relevance of PM2.5 exposure-regulatory abnormality-cardiovascular anomalies. By providing the epidemiological and experimental evidences for the relationship between PM2.5, its major components PAHs and fetal cardiovascular malformations, the present work will offer an important base for understanding the negative impacts of PM2.5 or its components on fetal cardiovascular development and their underlying mechanisms. The work will provide, more importantly, evidences and references to the environmental agency and governments for a validation of the currently revised criteria in the Chinese ambient pollutant standards, a gross planning objective and the necessity and strength of finance and power for comprehensive management of air pollution. It is also pivotal to birth defect monitoring & control and to maternal and infant care.

胎儿是大气细颗粒物（PM2.5）的易受伤害群体，其心血管系统是PM2.5不良效应的主要作用系统，但目前针对出生前PM2.5及其毒性成分暴露对胎儿心血管发育的不良效应及其作用机制的研究报道很少。项目制备并分析本地区PM2.5及其毒性组分多环芳烃（PAHs）样本，在大鼠出生前PM2.5或PAHs暴露模型上，观察标准允许浓度、高浓度PM2.5或PAHs暴露对胎鼠心血管发育的影响，探讨其作用机制。通过临床研究观察不同类型胎儿心血管畸形病例心血管发育敏感指标的变化，分析其与PM2.5暴露水平的关联性以与实验研究结果互为印证，阐释PM2.5暴露-心血管发育调控异常-心血管畸形发生的内在联系。该研究将明确出生前PM2.5及其主要毒性成分暴露对心血管发育的不良效应，阐释其作用机制，为大气污染治理的规划目标和力度、大气污染允许标准对胎儿发育的安全性提供判定依据，并为妊娠期母婴保健和优生优育施政提供重要参考。

项目针对大气PM2.5及其主要毒性成分多环芳烃提取物（EOM）出生前暴露对胎儿心血管发育的不良效应及其作用机制展开研究。采用本地区收集的PM2.5及其提取的EOM，在孕期滴注暴露模型上观察相当于我国大气污染标准允许水平及较高环境浓度的PM2.5或EOM暴露对胎鼠心血管发育的影响；初步观察心血管畸形临床病例相关指标变化及其与PM2.5暴露水平的关联性。. 研究结果显示，出生前相当于I级允许水平的低剂量暴露即可对胎鼠心血管发育产生多层面的不良效应：可使个体出生后心脏组织氧化还原关键酶SOD活性降低、凋亡相关基因Caspase3表达升高、细胞外基质重塑关键酶MMP9表达降低和组织代谢相关的ATP酶活力降低，调控心脏发育的转录因子Mef2c、Tbx5等和表观遗传修饰相关的DNMT1 DNMT3a/3b基因的表达均出现异常。该剂量PM2.5提取物EOM出生前暴露（7 ng/d）除了导致出生时氧化应激、凋亡相关基因和心脏转录基因表达的异常改变外，还可导致子代成年期（16周）氧化还原相关功能基因（16个）、血红素结合功能相关基因（13），以及铁离子结合、电子载体活动相关功能基因的差异表达，涉及的调节通路有物质代谢通路、胆固醇代谢等能量代谢通路、补体/凝血级联通路、吞噬体通路，可影响极低密度脂蛋白、胆固醇、高密度脂蛋白等的代谢。成年期仍存在的这些变化，增加了心血管等系统疾病的易感性。II级允许水平和更高剂量PM2.5及其提取物EOM出生前暴露对胎心发育的不良效应更为显著，除上述各层面更多指标出现异常外，中、高剂量暴露还可导致心肌细胞形态学及超微结构发生异常改变。. 上述结果表明，相当于大气污染I/II级允许水平的PM2.5暴露即可使仔鼠心脏发育出现异常，更高剂量暴露的不良效应更趋明显。一些不良效应持续到个体成年期仍存在。虽然本研究存在气道滴注暴露与真实环境吸入暴露有差异、得自动物实验的结论不能直接用于人类等不足，该研究仍可提示我国现行的空气污染允许水平（包括I级水平），对于易感群体是否适宜需要进一步评估。该研究结果可为判定大气污染允许标准对特定易感人群是否安全提供参考，进而为大气污染治理的目标和规划，为妊娠期母婴保健提供重要的科研数据。