Air Particulate Pollution and Stress: Effects and Mechanisms for Long-term Maternal Obesity Risks

总结 在怀孕期间，女性通常会增加16-40磅，并经历许多生理变化， 长期的后果。然而，关于怀孕作为环境敏感性窗口的研究 暴露主要集中在儿童身上，在很大程度上忽视了女性的长期体重增加， 心脏代谢健康新出现的肥胖风险因素包括通过可吸入细颗粒物起作用的空气污染 <2.5 μm（PM2.5）和心理社会压力。我们的初步数据确定怀孕是一个独特的窗口， 妇女对PM2.5和压力的脆弱性，表明怀孕期间空气污染和压力的影响 可能对女性一生的健康至关重要。怀孕需要一个新器官的发育- 胎盘长期以来被认为是胎儿编程的媒介。越来越多的证据 暗示微（mi）RNA作为这一过程的调节因子，但它们在长期母体编程中的作用， 没有被考虑。在以前的工作和我们的初步数据的支持下，我们假设， 在怀孕期间破坏胎盘滋养层细胞释放的miRNA信号， 将囊泡（EV）引入母体循环，使母体组织向肥胖和心脏代谢紊乱的方向发展。 条件据我们所知，空气污染和压力对怀孕期间母亲的共同影响并没有 EV-miRNAs作为潜在的长期妊娠特异性机制尚未被研究 控制产妇的结局。我们将在PROGRESS研究中解决这些差距， 墨西哥城的PM2.5暴露量高但可变，心理社会压力高。通过研究 PROGRESS招募怀孕的母亲，我们可以从2日起进行经济有效的纵向研究 怀孕后三个月到十年。我们还将进行最先进的血浆代谢分析 以增强识别早期代谢变化的能力。在目标1中，我们将确定 怀孕期间PM2.5暴露对产后1年体重保持以及肥胖（体重，BMI， 腰围/臀围，体脂%），心脏代谢生物标志物（血糖，胰岛素抵抗，脂质， 脂肪因子）和基于超声的亚临床颈动脉粥样硬化纵向测量超过10年。 在目标2中，我们将确定生活经历（暴力，抑郁， 负生活事件）和压力生物标志物（昼夜唾液皮质醇节律）在怀孕期间对这些相同的 肥胖和心脏代谢终点-独立和/或与较高的PM2.5暴露联合 怀孕在目标3中，我们将研究PM2.5和应激对胎盘特异性EV-miRNA的影响， 怀孕和妇女的代谢组1个月和4年后交付。在目标4中，我们将应用统计 因果建模，以表征EV-miRNA和代谢组学与PM2.5，压力，皮质醇 节律，以及母亲肥胖和心脏代谢健康。如果取得成功，我们的工作将推动采取干预措施， 可以帮助数百万女性预防体重和不良心脏代谢结果的终身变化。

SUMMARY In pregnancy, women typically gain 16-40 pounds and undergo numerous physiological changes with potentially long-lasting consequences. Yet, research on pregnancy as a window of susceptibility to environmental exposures has focused primarily on the child and largely overlooked women’s long-term weight gain and cardiometabolic health. Emerging risk factors for obesity include air pollution that acts via respirable fine particles <2.5 μm (PM2.5) and psychosocial stress. Our preliminary data identify pregnancy as a unique window of vulnerability to PM2.5 and stress for women, indicating that effects of air pollution and stress during pregnancy may be critical for women’s health over their lifecourse. Pregnancy requires the development of a new organ— the placenta—which has long been recognized as a mediator of fetal programming. Increasing evidence implicates micro (mi)RNAs as regulators of this process, but their role in long-term maternal programming has not been considered. Supported by previous work and our preliminary data, we hypothesize that exposures during pregnancy disrupt miRNA signals released by placental trophoblasts within nano-sized extracellular vesicles (EVs) into the maternal circulation, programming maternal tissues toward obesity and cardiometabolic conditions. To our knowledge, the joint effects of air pollution and stress on mothers during pregnancy have not been studied, nor have EV-miRNAs been investigated as potential long-term, pregnancy-specific mechanisms regulating maternal outcomes. We will address these gaps in the PROGRESS study, a high-risk population in Mexico City with high but variable PM2.5 exposure and high psychosocial stress exposure. By studying PROGRESS mothers recruited in pregnancy, we can cost-effectively conduct a longitudinal study from the 2nd trimester through 10 years after pregnancy. We will also conduct state-of-the-art plasma metabolomic profiling to enhance capacity of identifying early metabolic changes. In Aim 1, we will determine the impact of higher PM2.5 exposure during pregnancy on weight retention 1 year post-partum, as well as on adiposity (weight, BMI, waist/hip circumferences, body fat %), cardiometabolic biomarkers (blood glucose, insulin resistance, lipids, adipokines) and ultrasound-based measures of subclinical carotid atherosclerosis longitudinally over 10 years. In Aim 2, we will determine the impact of higher levels of stress from life experiences (violence, depression, negative life events) and stress biomarkers (diurnal salivary cortisol rhythms) during pregnancy on those same adiposity and cardiometabolic endpoints—independently and/or jointly with higher PM2.5 exposure during pregnancy. In Aim 3, we will investigate the impact of PM2.5 and stress on placenta-specific EV-miRNA during pregnancy and on the women’s metabolome 1 month and 4 years after delivery. In Aim 4, we will apply statistical causal modeling to characterize the patterns linking EV-miRNA and metabolomics with PM2.5, stress, cortisol rhythms, and maternal adiposity and cardiometabolic health. If successful, our work will impel interventions that may help millions of women to prevent lifelong changes in body weight and adverse cardiometabolic outcomes.