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.

产前对儿童哮喘和呼吸系统健康的规划可能受到母亲暴露的影响， 例如女性一生的压力，尽管这种生物嵌入的机制还没有完全被 描绘的。新出现的证据表明，暴露于创伤可能是一个特别强大的增强剂， 生物学事件增加了后代对哮喘的易感性，并可能有助于解释 低收入的美国城市人口。低收入BIPOC（黑人、土著人、有色人种）妇女 在他们的一生中经历创伤的比率高于美国国家样本。我们小组的研究表明 表明，妇女一生中暴露于创伤性压力源，即使是遥远的， 从产前开始规划呼吸道疾病。氧化应激（OS）由失衡引起 活性氧（ROS）和抗氧化防御之间的联系越来越被认为是发挥核心作用 在哮喘发病机制和肺生长发育中的作用。虽然有证据表明，BIPOC人口 增加了OS，研究检查了OS是否升高，使用传统生物标志物在既往研究中进行索引， 研究，部分解释了健康差异的好坏参半。不一致的结果可能是 选择先前研究中使用的生物标志物。此外，胎盘OS在胎儿编程中的关键作用是 随着高度依赖线粒体功能以维持最佳氧化剂平衡而日益受到重视。 慢性应激可导致线粒体过程功能障碍和ROS生成的积累。 线粒体因此，在多重组中部署的高阶生物标志物被认为是复杂的混合物。 和/或累积OS的生物标志物，可以提供对基础OS过程的更深入的了解， 在人群中。最后，新的证据表明OS和疾病结局之间的关系 可能受到潜在代谢因素的影响，这些因素因母亲种族/民族和体重指数而异 （BMI）。该提案将利用一个完善的城市、种族混合的纵向妊娠队列 一项研究旨在检查母亲终生压力、氧化应激生物标志物和儿童风险之间的关联 对于6-7岁时反复喘息和哮喘以及肺功能下降，评估 产后应激源和氧化应激生物标志物。母体产前OS将通过（i）中期- 妊娠尿氧化应激组（OS混合物）和（ii）胎盘线粒体DNA（mtDNA） 异质性拟议的分析将更全面地研究OS在产前诊断中的作用。 儿童哮喘和幼儿肺功能的规划，包括胎盘组织学。 解释母亲种族/民族和BMI的修饰效应可以更好地为观察到的差异提供信息。在 此外，阐明分子机制可能导致新的预防和治疗策略， 由于线粒体在调节母胎界面中的中心作用，我们的发现可能提供了一个 该模型可以扩展到额外的产前风险因素和其他胎儿疾病。