孕期PM2.5暴露致线粒体动力学稳态失衡与胎儿生长受限的关联性研究

Fetal growth restriction (FGR) is a common complication during pregnancy and is an important cause of perinatal death. Our previous studies have showed that exposure to PM2.5 during pregnancy will increase the risk of FGR, however, the relevant mechanism is not clear. Our pilot study has found that the expression of fusion genes and cleavage genes are changed by PM2.5 exposure in protein level, which will lead to mitochondrial dynamic imbalance and it has also been observed that the growth of the offspring produced by mice in high concentration exposure group are relatively backward. On basis of these clues, we will analyze the association between PM2.5 and FGR through the existing "Chinese labor cohort" and explore the mediator effect of mitochondrial dynamics imbalance in the association between PM2.5 and FGR through a case-control study in the cohort. The specific mechanism will be revealed by mice experiments using Asia's first "artificial climate environment warehouse" and be further validated via cell experiments. The expected outcomes will provide clues to the early identification and protection of PM2.5 health hazards, which are of great significance for the early warning and precise prevention of FGR.

胎儿生长受限（FGR）属于妊娠期常见并发症，是围生儿死亡的重要原因。我们前期研究发现孕期PM2.5暴露会增加FGR发生的风险，但相关机制不明。项目组预实验发现，高浓度PM2.5暴露致胎盘线粒体融合/裂解基因表达改变，线粒体动力学稳态失衡，同时观察到其仔鼠生长水平也较落后。基于上述发现，本项目拟以“中国产程研究”为基础构建孕妇队列，采用经时间调整的土地利用回归模型评估孕妇个体PM2.5暴露水平，随访胎儿“动态”生长轨迹，分析PM2.5暴露与FGR间关联性，明确各孕期暴露的疾病风险；同时嵌套巢式病例对照研究，分析线粒体动力学稳态失衡在上述关联性间的中介效应；在此基础上采用亚洲首个“人工气候环境暴露仓”开展孕鼠实验，揭示PM2.5致线粒体动力学稳态失衡的分子生物学机制并通过离体细胞实验进一步验证。预期成果将为PM2.5健康危害的早期识别及防护提供线索，对实现FGR早期预警和精细化预防有重要意义。

本研究从人群研究、动物实验、细胞学实验三个层次深入分析了PM2.5与FGR的关联性及基于线粒体功能的分子生物学机制。研究内容主要包括孕期PM2.5暴露与胎儿生长发育的关联性研究、小鼠PM2.5暴露实验和人胎盘组织及滋养细胞实验三个部分。.研究发现，孕期PM2.5暴露与胎儿大小间存在负关联，在控制了基本人口学信息、其它污染物和气象因素的情况下，PM2.5暴露每增加10ug/m3，胎儿的腹围、双顶径、股骨长分别平均减少5.48(9.06,1.91)mm、5.57(6.66,4.47)mm和5.47(6.39,4.55)mm，胎儿估计体重平均降低14.49(16.05,13.49)g。此外，孕期PM2.5暴露也与胎儿生长速度间存在负关联且该关联在孕21-32周较为明显。项目组发现，孕期PM2.5暴露组小鼠胎盘组织有642个基因上调，1266个基因表达下调，其中包括糖酵解相关基因PDK4、线粒体有氧代谢相关基因ALDH1A3、ALDH1B1等。小鼠PM2.5孕前暴露实验结果显示，孕前PM2.5暴露增加了卵母细胞中的活性氧(ROS)水平(45.39±0.82vs.24.20±0.85,p<0.01)。RNA测序转录谱分析结果显示，孕前PM2.5暴露组和对照组小鼠卵母细胞中存在广泛的基因异常表达，尤其是那些涉及调节卵母细胞线粒体呼吸复合体和囊胚代谢过程的基因。此外，研究发现孕前PM2.5暴露母鼠所产仔鼠的出生身长(6.00±0.37vs7.00±0.26,p<0.05)和体重(1.18±0.02vs1.27±0.02g,p<0.01)均低于对照组。.截至目前，本项目在Journal of hazardous materials(环境科学与生态学1区)、International Journal of Epidemiology(医学1区)、Environmental Pollution、Chemosphere、Environmental Health等知名期刊上发表SCI论文9篇，合计影响因子超过50。本项目对实现FGR的早期预警和精细化预防具有重要意义。此外，本研究通过非参数函数模型拟合胎儿生长速度曲线，首次从“胎儿生长速度”的角度评估PM2.5孕期暴露对胎儿生长发育的影响，为PM2.5健康危害效应的研究提供了新的评估指标和切入点。