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.

儿童哮喘和呼吸系统健康的产前规划可能受到母亲接触的影响， 例如女性一生的压力，尽管这种生物嵌入的机制尚未完全阐明 新出现的证据表明，遭受创伤可能是一种特别强大的促进因素。 增加后代患哮喘的可能性的生物事件可能有助于解释以下发现的风险增加 美国城市低收入人口 低收入 BIPOC（黑人、土著、有色人种）女性。 一生中经历创伤的比率高于我们小组的研究显示的美国全国样本。 研究表明，女性一生中暴露于创伤性压力源，即使是在遥远的地方，也会影响与压力相关的压力 因不平衡而导致的氧化应激（OS）的呼吸系统疾病的规划从产前开始。 人们越来越多地认为活性氧（ROS）和抗氧化防御之间发挥着核心作用 有证据表明 BIPOC 人群具有哮喘发病机制和肺部生长发育的作用。 OS 增加，研究检查 OS 是否升高，在之前使用传统生物标志物进行索引 研究部分解释了健康差异的结果可能是不一致的。 此外，胎盘操作系统在胎儿编程中发挥的关键作用是选择先前研究中使用的生物标志物。 由于高度依赖线粒体功能来维持最佳的氧化平衡，因此越来越受到重视。 慢性应激可导致线粒体过程功能失调和 ROS 生成的积累 因此，多重组中部署的高级生物标志物被视为复杂的混合物。 和/或累积操作系统的生物标记，可以更深入地了解不同的底层操作系统进程 最后，新出现的证据表明 OS 与疾病结果之间的关系。 可能会因潜在的代谢因素而改变，这些因素因母亲的种族/民族和体重指数而异 (BMI)。该提案将利用成熟的城市、种族混合纵向妊娠队列。 研究检查母亲一生压力、氧化应激生物标志物和儿童风险之间的关联 6-7 岁时反复喘息和哮喘以及肺功能下降，评估以下因素的联合影响 产后应激源和氧化应激生物标志物将通过 (i) 中期指标进行索引。 妊娠尿氧化应激组（OS 混合物）和 (ii) 胎盘线粒体 DNA (mtDNA) 所提出的分析将更全面地研究 OS 在产前的作用。 儿童哮喘和幼儿肺功能（包括胎盘线粒体）的编程。 考虑到母亲种族/民族和体重指数的影响，可以更好地了解观察到的差异。 此外，阐明分子机制可能会带来新的预防和治疗策略， 由于线粒体在调节母胎界面中的核心作用，我们的研究结果可能提供 该模型可以扩展到其他产前危险因素和其他胎儿疾病。