Epigenetic Mediation of Prenatal Tobacco and Alcohol Exposure and Infant Neurodevelopment in a South African Birth Cohort: A High-Dimensional Mediation Analysis

BACKGROUND AND AIMS Prenatal tobacco exposure (PTE) and prenatal alcohol exposure (PAE) have been associated with an increased risk of delayed neurodevelopment in children as well as differential newborn DNA methylation (DNAm). However, the biological mechanisms connecting PTE and PAE, DNAm, and neurodevelopment are largely unknown. Here we aim to determine whether differential DNAm in cord blood mediates the association between PTE and PAE and neurodevelopment in 113 children of 6 months of age from the South African Drakenstein Child Health Study. METHODS PTE and PAE were assessed antenatally using urine cotinine measurements and the ASSIST questionnaire, respectively. DNAm was measured from cord blood using the EPIC and 450K BeadChips. Neurodevelopment was measured at 6 months across five domains (cognitive, language, motor, adaptive behavior, socioemotional) using the Bayley Scale of Infant and Toddler Development, Third Edition. We conducted a high-dimensional mediation analysis using a novel approach called the divide-aggregate composite null test (DACT), followed by causal mediation analysis to estimate the average causal mediation effects (ACME) and total effect (TE). RESULTS In this population, 35% of mothers actively smoked and 23% of mothers consumed alcohol during pregnancy. We identified 31 CpG sites and 8 CpG sites to have a significant mediating effect (ACME and TE P <0.05) between PTE and cognitive and motor development, respectively. For PAE, 16 CpG sites and 1 CpG site had a significant mediating effect on motor and adaptive behavior development, respectively. CONCLUSIONS These findings suggest that changes in the methylome may in part explain the biological mechanisms underlying the relationship between PTE and PAE and infant neurodevelopment. The identification of significant CpG sites could provide novel insights for early detection of disease and potential prevention targets in translational research and community interventions in at-risk populations. KEYWORDS: epigenomics; mediation analysis; neurodevelopment; prenatal smoking; prenatal alcohol exposure