妊娠期PM2.5暴露导致宫内胚胎生长受限的毒理效应与系统生物学研究

Intrauterine growth restriction (IUGR) refers to poor growth of a fetus while in the mother's womb during pregnancy. The causes can be many, and include exposure to ambient air pollutant. IUGR is linked to postnatal development abnormality and disease risks. Fine particles (e.g., PM2.5) are important components in air pollution in China, and attracted increasing concerns regarding to their adverse impact on human health. Pregnant women and fetus in uterus are particular susceptible to toxic pollutants; however, the impact of PM2.5 in China and its chemical components on IUGR risk is poorly studied. This proposal is consist of three inter-connected aims. (1) We take advantage of the established systems in investigators’ labs at Tongji University to synthesize the primary components of PM2.5 in China. The concentration, diameter and chemical composition of the PM2.5 is precisely controlled in the lab. Pregnant mice will be exposure to the synthesized PM2.5 in specially designed chambers, where the exposure conditions are closely monitored in real-time. Four PM2.5 components along with Shanghai ambient air and filtered clean air will be given to identical groups of mice. We will also investigate the susceptibility to PM2.5 during early stage of pregnancy and middle stage of pregnancy, which are critical periods of blastocyst formation, implantation and organogenesis. (2) Phenotype will be measured at birth (birth count, birth weight, placenta weight and gestational age). Placenta is the key organ controlling the access of oxygen and nutrition to the fetus, as well as toxic chemicals. Placenta tissue will be collected from each exposure group, and profiled for whole transcriptome and DNA methylation. (3) We will conduct systems biology analysis aiming to understand the molecular mechanisms (gene, pathway, co-expression networks, etc) that PM2.5 exposure alternate placenta function and result in IUGR. The analysis also identifies biomarker in placenta which indicate the damage due to PM2.5 exposure during pregnancy.

胚胎宫内生长受限（IUGR）是指在子宫内生长缓慢。IUGR会进一步导致新生儿后天发育迟缓等异常。妊娠期大气污染物暴露是IUGR的重要诱因。同时，妊娠期妇女的PM2.5的暴露损伤，也是我国公众关心的问题。目前PM2.5暴露导致IUGR的研究多是在西方进行的。我国典型地区大气PM2.5对妊娠期体内胎儿的影响程度及诱发IUGR的风险，存在诸多研究空白。本项目旨在检测如下假设：我国PM2.5和主要组分，具有妊娠期暴露导致IUGR的毒理作用，且胎盘为主要介导器官。 为此，(一)我们建立动物模型，开展妊娠期PM2.5暴露试验，试验条件包括: 洁净空气，自然大气，以及PM2.5主要组分。(二)测量妊娠期PM2.5后幼鼠发育表型：孕期长度，出生体重等。 (三)胎盘组织的生物分子组学，利用系统生物组学方法，阐明妊娠期PM2.5暴露影响胎盘发育和功能，进而导致IUGR的细胞和分子毒理机制。

胚胎宫内生长受限（IUGR）是指在子宫内生长缓慢, 并且会导致新生儿多种后天疾病风险升高。妊娠期大气污染物暴露是IUGR的诱因之一。本研究按照年度计划顺利执行并完成，共进行了三个领域的工作并取得重要结果。(1) 建立上海市第十人民医院新生儿出生队列(678个母婴对) 和验证队列(227个母婴对)。系统收集孕产妇健康，胚胎发育、出生表型的数据。我们发现，孕期PM2.5，PM10和SO2 暴露会改变胚胎发育进程，显著降低第24孕周的胚胎的股骨长度（FL），肱骨长度（HL），腹围（AC）。暴露导致24周胚胎体重减轻了6.3％（p = 3.5e-5），而胎儿躯干重量减小了7.9％（p = 7.3E-9）。胎盘功能下降，是这种“不对称生长限制”的重要致病机制。(2) 开展可控条件下的动物模型暴露实验，亲本小鼠（雄性和雌性）孕前和妊娠期暴露于我国大气PM2.5中主要的三种主要水溶性无机盐组分(铵根离子，硫酸根离子，硝酸根离子) 。子代小鼠出生后，在洁净空气中生长。我们发现孕前和妊娠期PM2.5暴露显著损伤子代小鼠的后天呼吸功能。FEV0.05/FVC 降低是阻塞性呼吸道疾病的核心特征。PM2.5 NH4+、SO42-和NO3-暴露组的子代小鼠的FEV0.05/FVC分别比对照组低19.1%（p=6.1e-5）、16.1%（p=8.6e-3）和8.9%（p=4.6e-3）。这部分工作证明，孕前和妊娠期暴露不可逆地损害的胚胎呼吸系统的形成和发育， 并大幅度降低的成年后的呼吸功能。(3) 动物模型暴露实验 发现孕前和妊娠期PM2.5暴露导致雄性和雌性生殖器官减小、孕期缩短、子代个数减少，并显著降低子代出生体重。课题组解析了胎盘基因表达谱，发现宫内缺氧反应(hypoxia)可能是孕前和妊娠期暴露致病效应的分子机制。综上，本研究利用上海地区人群队列和动物暴露实验阐明了妊娠期PM2.5暴露导致显著的胚胎发育受限和后天疾病风险，并在分子水平提出了致病机制。结果对防治与预测PM2.5污染对人民健康的危害有直接的指导作用。本课题产出SCI 论文 8 篇, 培养博士生1人，硕士生1人。 参加国际国内会议3次，并作口头汇报 3人次。