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

儿童哮喘和呼吸健康的产前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 勾勒出来的。新出现的证据表明，暴露在创伤中可能是一种特别强大的增强剂 生物事件增加了后代患哮喘的易感性，并可能有助于解释在 低收入的美国城市人口。低收入BIPOC(黑人、土著、有色人种)妇女 在他们一生中经历创伤的比率高于美国全国样本。我们小组的研究已经 研究表明，女性终生暴露在创伤性应激源中，即使是在遥远的情况下，也会影响与压力有关的因素 从产前开始规划呼吸系统疾病。失衡导致的氧化应激(OS) 在活性氧簇(ROS)和抗氧化剂防御之间，越来越多的人被认为起着核心作用 在哮喘发病机制和肺的生长发育中起重要作用。而有证据表明，BIPOC种群 增加了操作系统，研究检查提升的操作系统是否在以前使用传统生物标记物进行索引 研究在一定程度上解释了健康差距的好坏参半。不一致的结果可能是 选择先前研究中使用的生物标记物。此外，胎盘OS在胎儿编程中扮演的关键角色是 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，部署在被视为复杂混合物的多路面板中的更高阶生物标志物 和/或累积操作系统的生物标志物，可以更好地洞察不同的底层操作系统进程 在不同人群之间。最后，新出现的证据表明，OS和疾病结局之间的关系 可能会受到潜在的代谢因素的影响，这些因素会因母亲的种族/民族和体重指数而异 (BMI)。这项提议将利用一个成熟的城市、种族混杂的纵向怀孕队列。 一项考察母亲一生应激、氧化应激生物标记物和儿童患病风险之间关系的研究 用于6-7岁反复喘息、哮喘和肺功能减退的联合疗效评估 出生后应激源和氧化应激生物标记物。母体产前OS将通过(I)中期 妊娠期尿氧化应激板(OS混合物)和胎盘线粒体DNA(MtDNA) 异质性。拟议的分析将更全面地检查OS在产前中的作用 儿童哮喘和儿童早期肺功能的规划，包括胎盘线粒体组学。 考虑到母亲种族/民族和BMI的修正影响，可能会更好地了解观察到的差异。在……里面 此外，阐明分子机制可能导致新的预防和治疗策略和 由于线粒体在调节母胎界面中的核心作用，我们的发现可能会提供一种 该模型可以扩展到附加的产前危险因素和其他胎儿障碍。

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.