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

摘要 在怀孕期间，女性通常会增加16-40磅，并经历许多生理变化，有可能 造成长期后果。然而，关于怀孕作为环境易感性窗口的研究 暴露主要集中在孩子身上，而在很大程度上忽视了妇女的长期体重增加和 心脏代谢健康。新出现的肥胖风险因素包括通过可呼吸细颗粒物作用的空气污染 &lt；2.5μm(PM2.5)和心理社会压力。我们的初步数据显示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 可能在女性的一生中对她们的健康至关重要。怀孕需要发育一个新的器官-- 胎盘--长期以来一直被认为是胎儿程序化的中介物。越来越多的证据 暗示微(Mi)RNA是这一过程的调节者，但它们在长期母体编程中的作用 没有被考虑过。在之前的工作和我们的初步数据的支持下，我们假设 妊娠期间干扰胎盘滋养层细胞内纳米级细胞外释放的miRNA信号 囊泡(EV)进入母体循环，使母体组织朝着肥胖和心脏新陈代谢方向发展 条件。据我们所知，怀孕期间空气污染和压力对母亲的联合影响并没有 EV-miRNAs已被研究过，也没有被作为潜在的长期妊娠特异性机制进行研究 调节产妇的结局。我们将在进展研究中解决这些差距，高危人群在 墨西哥城PM2.5暴露水平较高但变化较大，心理社会压力暴露较高。通过研究 在怀孕期间招募母亲的进展，我们可以从2日开始进行一项具有成本效益的纵向研究 怀孕三个月至怀孕后10年。我们还将进行最先进的血浆代谢组学分析 提高识别早期代谢变化的能力。在目标1中，我们将确定更高 孕期PM2.5暴露与产后一年体重保持以及肥胖(体重、BMI、 腰围/臀围、体脂百分比)、心脏代谢生物标志物(血糖、胰岛素抵抗、血脂、 脂肪因子)和基于超声的亚临床颈动脉粥样硬化的纵向测量超过10年。 在目标2中，我们将确定来自生活经历的更高水平的压力(暴力、抑郁、 负性生活事件)和孕期应激生物标志物(昼夜唾液皮质醇节律) 肥胖和心脏代谢终点--独立和/或联合暴露于较高的PM2.5 怀孕了。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 妊娠及产后1个月和4年对妇女代谢的影响。在目标4中，我们将应用统计学 EV-miRNA和代谢组学与PM2.5、应激、皮质醇之间的因果模型 节律、母亲肥胖症和心脏代谢健康。如果成功，我们的工作将推动干预行动 可以帮助数百万妇女预防体重的终生变化和心脏代谢的不良后果。

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.