A polyepigenetic glucocorticoid exposure score and HPA axis-related DNA methylation are associated with gestational epigenetic aging.

Gestational epigenetic aging (GEA) is a novel approach for characterizing associations between prenatal exposures and postnatal risks. Psychosocial adversity in pregnancy may influence GEA, but the molecular mechanisms are not well understood. DNA methylation to glucocorticoid regulation and hypothalamic-pituitary-adrenal (HPA) axis genes are implicated but have not been fully examined in association with GEA. This study investigated whether a polyepigenetic glucocorticoid exposure score (PGES) and HPA axis gene (NR3C1, HSD11B2, FKBP5) methylation were associated with GEA, and whether associations were sex-specific. Participants were from a prospective cohort of racial/ethnic diverse and socially disadvantaged pregnant women and infants (n = 200). DNA methylation variables were estimated using umbilical cord blood. PGES was derived with CpGs shown to be sensitive to synthetic dexamethasone exposure. NR3C1, HSD11B2, and FKBP5 methylation was summarized via factor analysis. We found that PGES (β = -1.12, SE = 0.47, p = 0.02) and several NR3C1 and FKBP5 factor scores were associated with decelerated GEA (all p < 0.05). A significant sex interaction was observed for FKBP5 factor score 3 (β = -0.34, SE = 0.15, p = 0.02) suggesting decelerated GEA for males but not females. This study showed that glucocorticoid regulation-related DNA methylation was associated with a decelerated aging phenotype at birth that might indicate a neonatal risk.