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

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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.