DNA methylation differences associated with prenatal air pollution exposure in developmentally relevant tissues from two North American birth cohorts

Prenatal air pollutant exposures are linked to childhood atopic diseases like wheeze and asthma. The molecular mechanisms are not fully understood, but likely involve lasting changes to epigenetic marks, such as DNA methylation (DNAm). Newborn cord blood and placenta DNAm differences have been demonstrated, but few studies interrogated their role in health outcomes. Additionally, these investigations primarily involved participants of European descent, limiting broader applicability. This thesis addresses these gaps using microarray data and an epigenome wide approach to profile cord blood and placenta DNAm differences associated with air pollutant exposures (NO2, PM2.5, and PM10) in two diverse North American cohorts. This work identified novel differentially methylated regions (DMRs) in both tissues and replicated previous findings in cohorts from similar backgrounds. Notably, a DMR in the lung development gene HOXA5 was observed in both cohorts, with DNAm differences likely driven by changes in biological males. Most DMRs were tissue-specific, reflecting the distinct roles of cord blood and placenta in development and disease, with minimal overlap between pollutants, suggesting unique mechanistic effects. Causal mediation analysis highlighted trends for cord blood DMRs in the association between PM2.5 exposure and transient wheeze, and placental DMRs in persistent wheeze with PM2.5, indicating different roles for these tissues in respiratory health. Additionally, this thesis examined the persistence of DNAm changes, finding that most cord blood DMRs associated with prenatal NO2 exposure remained significant at age one, implying greater potential to impact later health. This work also introduced a novel subtractive method leveraging repeated DNAm measures to identify a postnatal-specific DMR related to NO2 in the first year of life, reinforcing the susceptibility of early developmental stages to environmental factors. Finally, given that air pollution likely exerts its effects through oxidative stress and ...