Air Pollution, Inflammation and Preterm Birth: A Mechanistic Study in Mexico City

描述（由申请人提供）： 早产是围产期死亡的主要原因，并与存活婴儿的长期不良健康后果有关。目前还没有预防早产的有效手段，随着美国和世界各地早产率的上升，调查可能的因果机制是全球公共卫生的优先事项。医学研究所最近的一份报告指出，空气污染暴露可能是早产的一个重要原因，但大多数已发表的研究都是基于人口出生登记，缺乏阐明介导这些流行病学关联的可能生物学机制所需的个人临床数据。这项拟议的工作提供了一个独特的机会，可以在居住在墨西哥城不同地区的800名孕妇中研究这些机制，墨西哥城是一个空气污染程度很高的特大城市。研究人员将通过调查空气污染和炎症如何共同影响妊娠结果，以及某些妊娠期是否代表临床和环境预防干预的关键时间窗口和机会，来促进对早产的理解。研究人员将获得参与者在怀孕期间每月提供的宫颈阴道分泌物中与炎症和早产相关的生物标志物（IL-1、IL-1 ra、IL-6、IL-8、IL-10、TNF-α），沿着感染、健康史、临床特征、饮食和时间活动模式的信息。将采用最先进的接触评估技术，利用墨西哥城都市区空气质量监测网络（PM2.5、PM10、臭氧、二氧化氮、二氧化硫、一氧化碳）提供的数据，与参与者的住所位置相匹配，评估空气污染接触的空间和时间变异性。在出生时，来自母亲和婴儿的DNA样本将用于对与早产风险增加相关的三种遗传细胞因子多态性（TNF-α，IL-1？，IL-1 ra）进行分型。研究人员将评估环境污染是否与早产有关，控制其他风险因素;它们是否与怀孕期间的细胞因子有关，以及哪些时间窗口最相关。研究者将通过摄入抗氧化维生素（E和C）和细胞因子多态性来检查效果改变。最后，研究人员将通过一项平行的毒理学体外研究来补充这项流行病学研究，该研究将涉及每月从MCMA的五个区域收集和表征空气污染颗粒物样本（PM10和PM2.5），并暴露单核细胞系（J774A.1）以评估相同细胞因子的表达。人类和体外证据之间的任何一致性，污染和这些介导分子之间的机械关联将指导未来的研究。这种多学科的全球卫生合作将评估早产的潜在环境和临床决定因素，目标是开发具有深远预防意义的独特知识。

DESCRIPTION (provided by applicant): Preterm birth is the leading cause of perinatal mortality and is associated with long-term adverse health consequences for surviving infants. No effective means for prevention of prematurity currently exists, and with preterm birth rates rising in the United States and worldwide, investigating possible causal mechanisms is a global public health priority. A recent Institute of Medicine Report notes that air pollution exposure may be a significant cause of prematurity, but most published studies are based on population birth registries and lack the individual, clinical data needed to elucidate possible biological mechanisms mediating these epidemiological associations. This proposed work presents a unique opportunity to study those mechanisms in a new cohort of 800 pregnant women residing in diverse regions of Mexico City, a mega-city with high air pollution levels. The investigators will advance the understanding of prematurity by investigating how air pollution and inflammation may act together to influence the outcome of pregnancy, and whether certain periods of gestation represent critical time windows and opportunities for preventive interventions, both clinical and environmental. The investigators will obtain biomarkers relevant to inflammation and preterm delivery (IL-1¿, IL-1ra, IL-6, IL-8, IL-10, TNF-a) in cervico-vaginal exudates provided by participants monthly during their pregnancies, along with information on infections, health history, clinical characteristics, diet and time-activity patterns. State-of-the-art exposure assessment techniques will be used to evaluate spatial and temporal variability in air pollution exposure using data from the Mexico City Metropolitan Area (MCMA) air quality monitoring network (PM2.5, PM10, ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide), matched to locations of participants' homes. At birth, DNA samples from mother and infant will be used to type three genetic cytokine polymorphisms (TNF-a, IL-1¿, IL- 1ra) that have been associated with enhanced risk of preterm birth. The investigators will evaluate whether ambient pollution is associated with preterm birth, controlling for other risk factors; whether they are associated with cytokines during pregnancy, and which time windows are most relevant. The investigators will examine effect modification by intake of antioxidant vitamins (E and C) and cytokine polymorphisms. Finally, the investigators will complement this epidemiological study with a parallel toxicology in vitro study which will involve collecting and characterizing air pollution particle samples (PM10 and PM2.5) on a monthly basis from five zones in MCMA and exposing a monocytic cell line (J774A.1) to evaluate expression of the same cytokines. Any coherence between the human and in vitro evidence for a mechanistic association between pollution and these mediating molecules will guide future studies. This multi-disciplinary, global health collaboration will evaluate potential environmental and clinical determinants of preterm delivery, with the goal of developing unique knowledge with far-reaching prevention implications.