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

空气颗粒污染和压力：对孕产妇长期肥胖风险的影响和机制

• 批准号: 10432095
• 负责人: Andrea Baccarelli
• 金额: $ 44.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10432095
• 关键词: Acids; Address; Adrenal Glands; Affect; Air; Air Pollution; Anthropometry; Atherosclerosis; Biological Markers; Blood; Blood Circulation; Blood Glucose; Blood Pressure; Body Weight; Body fat; Body mass index; C-reactive protein; Carotid Atherosclerotic Disease; Child; Child Health; Cities; Data; Development; Diet; Diet Habits; Dietary Questionnaires; Elderly; Encapsulated; Environment; Environmental Exposure; Event; Fasting; Fetus; Future; Glycoproteins; Grant; Growth; Health; High Density Lipoprotein Cholesterol; Hip region structure; Hydrocortisone; Hypothalamic structure; Inflammatory; Insulin Resistance; Intervention; Joints; Life; Life Experience; Life Stress; Link; Lipids; Longitudinal Studies; Measures; Mediator of activation protein; Mental Depression; Metabolic; Metabolism; Mexico; MicroRNAs; Mothers; Obesity; Organ; Outcome; Particulate; Pathway interactions; Pattern; Physiological; Pituitary Gland; Placenta; Plasma; Pollution; Postpartum Period; Predisposition; Pregnancy; Pregnancy Trimesters; Process; Psychosocial Stress; Public Health; Research; Resources; Risk Factors; Role; Salivary; Sampling; Second Pregnancy Trimester; Signal Transduction; Stress; Testing; Time; Tissues; Triglycerides; Violence; Weight; Weight Gain; Woman; Women' s Health; Work; adipokines; air filter; base; cardiometabolism; carotid intima-media thickness; causal model; child bearing; cost; experience; extracellular vesicles; fetal programming; fine particles; follow-up; high risk population; indoor air; inflammatory marker; maternal obesity; maternal outcome; maternal weight; metabolome; metabolomics; microRNA biomarkers; nanosized; obesity risk; prevent; recruit; social stressor; stress reduction; trophoblast; ultrasound; vesicular release

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.

概括 在怀孕期间，女性通常会增加 16-40 磅，并经历许多生理变化，这些变化可能会导致 长期持续的后果。然而，关于怀孕作为环境易感性窗口的研究 暴露主要集中在儿童身上，很大程度上忽视了女性的长期体重增加和 心脏代谢健康。肥胖的新风险因素包括通过可吸入细颗粒作用的空气污染 <2.5 μm (PM2.5) 和社会心理压力。我们的初步数据表明怀孕是一个独特的窗口期 女性容易受到 PM2.5 和压力的影响，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。怀孕需要新器官的发育—— 胎盘——长期以来一直被认为是胎儿编程的调节者。越来越多的证据 暗示 micro (mi)RNA 作为这一过程的调节者，但它们在长期母体编程中的作用已经 没有被考虑。在之前的工作和我们的初步数据的支持下，我们假设暴露 怀孕期间破坏胎盘滋养层纳米级细胞外释放的 miRNA 信号 囊泡 (EV) 进入母体循环，对母体组织进行编程以实现肥胖和心脏代谢 状况。据我们所知，空气污染和压力对母亲怀孕期间的联合影响尚未 尚未研究过，也没有研究过 EV-miRNA 作为潜在的长期、妊娠特异性机制 调节产妇结局。我们将在 PROGRESS 研究中解决这些差距，这是一个高风险人群 墨西哥城 PM2.5 暴露量较高但变化较大，社会心理压力也较高。通过学习 PROGRESS 招募怀孕期间的母亲，我们可以从 2 号开始经济高效地进行纵向研究 怀孕后三个月到十年。我们还将进行最先进的血浆代谢组学分析 增强识别早期代谢变化的能力。在目标 1 中，我们将确定更高的影响 怀孕期间接触 PM2.5 对产后 1 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、 怀孕期间的负面生活事件）和压力生物标志物（昼夜唾液皮质醇节律） 肥胖和心脏代谢终点——独立地和/或与较高的 PM2.5 暴露同时发生 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 怀孕期间以及产后 1 个月和 4 年后女性代谢组的变化。在目标 4 中，我们将应用统计 因果模型来描述 EV-miRNA 和代谢组学与 PM2.5、压力、皮质醇之间的联系模式 节律、母亲肥胖和心脏代谢健康。如果成功，我们的工作将推动干预措施 可能有助于数百万女性预防终生体重变化和不良心脏代谢结果。