Associations among maternal lifetime psychosocial stress, prenatal systemic and placental oxidative stress mixtures, and child asthma

母亲一生心理社会压力、产前全身和胎盘氧化应激混合物与儿童哮喘之间的关联

• 批准号: 10660716
• 负责人: KECIA Nicole CARROLL
• 金额: $ 76.23万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660716
• 关键词: Accounting; Address; Age; Antioxidants; Asthma; Biological; Biological Clocks; Biological Markers; Biological Process; Black, Indigenous, People of Color; Body mass index; Cells; Child; Childhood Asthma; Chronic stress; Cohort Studies; Complex Mixtures; Detection; Disease Outcome; Disparity; Environmental Risk Factor; Equilibrium; Ethnic Origin; Ethnic Population; Event; Exposure to; F2-Isoprostanes; Fetal Diseases; Genome; Growth and Development function; Individual; Interpersonal Violence; Investigation; Isomerism; Joints; Life Cycle Stages; Lipid Peroxidation; Low income; Lung; Maternal Exposure; Maternal-Fetal Exchange; Measures; Mediating; Metabolic; Mitochondria; Mitochondrial DNA; Modeling; Modification; Molecular; Mothers; Mutate; Obesity; Overweight; Oxidants; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Placenta; Play; Population; Population Heterogeneity; Pregnancy; Prevention strategy; Process; Production; Psychosocial Stress; Race; Reactive Oxygen Species; Research; Respiratory Disease; Risk; Role; Sampling; Site; Stress; Time; Trauma; Wheezing; Woman; Work; biomarker selection; cohort; disorder risk; early childhood; ethnic diversity; experience; fetal programming; health disparity; heteroplasmy; in utero; indexing; insight; mitochondrial DNA mutation; mitochondrial dysfunction; novel; novel marker; offspring; people of color; postnatal; prenatal; prenatal risk factor; prepregnancy; psychosocial stressors; pulmonary function; racial diversity; racial population; respiratory health; sex; stressor; trauma exposure; treatment strategy; urinary

Prenatal programming of child asthma and respiratory health is potentially influenced by maternal exposures, such as a woman’s lifetime stress, although mechanisms of this biologic embedding have not been fully delineated. Emerging evidence suggests that exposure to trauma can be a particularly robust potentiator of biological events that increase vulnerability to asthma in offspring and may help explain increased risk found in lower-income urban U.S. populations. Lower-income BIPOC (Black, Indigenous, People of Color) women experience traumas over their lifetime at rates above national U.S. samples. Research from our group has shown that lifetime exposure to traumatic stressors in women, even when remote, impact stress-related programming of respiratory disease starting prenatally. Oxidative stress (OS) resulting from an imbalance between reactive oxygen species (ROS) and antioxidant defenses is increasingly thought to play a central role in asthma pathogenesis and lung growth and development. While evidence indicates that BIPOC populations have increased OS, studies examining whether elevated OS, indexed using traditional biomarkers in prior studies, in part explains health disparities have been mixed. Inconsistent findings may be a consequence of select biomarkers used in prior studies. Moreover, the critical role placental OS plays in fetal programming is increasingly appreciated with a high reliance on mitochondrial function to maintain optimal oxidant balance. Chronic stress can result in dysfunctional mitochondrial processes and the accumulation of ROS-generating mitochondria. Thus, higher order biomarkers deployed in multiplex panels considered as complex mixtures and/or biomarkers of cumulative OS, may provide greater insight into underlying OS processes that vary across populations. Finally, emerging evidence suggests that relationships between OS and disease outcomes may be modified by underlying metabolic factors that vary by maternal race/ethnicity and body mass index (BMI). This proposal will leverage a well-established urban, ethnically mixed longitudinal pregnancy cohort study to examine associations among maternal lifetime stress, oxidative stress biomarkers, and children’s risk for repeated wheeze and asthma and reduced lung function by age 6-7 years assessing for joint effects of postnatal stressors and oxidative stress biomarkers. Maternal prenatal OS will be indexed by (i) a mid- pregnancy urinary oxidative stress panel (OS mixtures) and (ii) placental mitochondrial DNA (mtDNA) heteroplasmy. The proposed analyses will more comprehensively examine the role of OS in prenatal programming of child asthma and early childhood lung function including placental mitochondriomics. Accounting for modifying effects of maternal race/ethnicity and BMI may better inform observed disparities. In addition, elucidating molecular mechanisms may lead to novel prevention and treatment strategies and because of the central role of mitochondria in regulating the maternal-fetal interface, our findings may provide a model that can be extended to additional prenatal risk factors and other fetal disorders.

儿童哮喘和呼吸健康的产前编程可能受到母亲暴露的影响， 例如女人的一生压力，尽管这种生物嵌入的机制尚未完全 描绘。新兴的证据表明，暴露于创伤可能是 生物事件增加了后代哮喘的脆弱性，并可能有助于解释增加的风险 低收入城市人口。低收入BIPOC（黑色，土著，有色人种）女性 以高于美国国家样本的速度经历创伤。我们小组的研究有 表明，即使远程影响压力有关 从产前开始呼吸道疾病的编程。因失衡而导致的氧化应激（OS） 越来越多地认为，活性氧（ROS）和抗氧化剂的防御能力越来越被认为起着核心作用 在哮喘发病机理和肺部生长和发育中。虽然证据表明BIPOC人群 增加了操作系统，研究了是否在先前使用传统生物标志物进行索引的OS是否索引 研究，部分解释了健康分布。不一致的发现可能是 选择先前研究中使用的生物标志物。此外，胎儿编程中的关键作用是 越来越多地保留了线粒体功能以保持最佳氧化物平衡。 慢性应激会导致功能失调的线粒体过程和ROS-生成的积累 线粒体。那是在被视为复杂混合物的多重板中部署的高阶生物标志物 和/或累积OS的生物标志物，可能会提供更深入的洞察力，以了解不同的OS过程 跨种群。最后，新兴的证据表明OS与疾病结局之间的关系 可能因母体种族/种族和体重指数而变化的潜在代谢因素来改变 （BMI）。该提议将利用一个公认的城市，种族混合的纵向怀孕队列 研究以检查产物寿命压力，氧化应激生物标志物和儿童风险之间的关联 对于重复的Wheeleze和哮喘以及到6-7岁时的肺功能降低，评估关节影响 产后应激源和氧化应激生物标志物。孕产妇的产前操作系统将由（i）中期索引 妊娠尿氧化应激面板（OS混合物）和（ii）胎盘线粒体DNA（mtDNA） 异质。提出的分析将更全面地检查OS在产前的作用 儿童哮喘和幼儿肺功能的编程，包括胎盘线粒体。 考虑到孕产妇/种族和BMI的修改影响可能会更好地告知观察到的差异。在 此外，阐明分子机制可能会导致新的预防和治疗策略，并且 由于线粒体在调查母体界面中的核心作用，我们的发现可能提供 可以扩展到其他产前危险因素和其他胎儿疾病的模型。