Early pregnancy metal exposure and epigenetic aging biomarkers at birth and in childhood in a US cohort

Abstract

Background and Aim: Epigenetic aging is a strong predictor of mortality and morbidity, potentially linking environmental exposures to health. We analyzed the extent to which prenatal metals were associated with epigenetic age acceleration (EAA) at birth and in childhood in the Project Viva cohort. Methods: Metal concentrations (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, Zn) were measured in maternal erythrocytes. DNA methylation was measured in cord blood (N=361) and leukocytes in early (N=92, median=3.2 years) and mid-childhood (N=333, median=7.7 years). We calculated epigenetic clocks for gestational age (GA) (Bohlin clock), early- and mid-childhood age (Horvath and skin & blood clocks), and respective EAA measures. Horvath intrinsic EAA adjusting for estimated cell types was also calculated. We evaluated associations between each metal and EAA at each period using linear models and across ages using linear mixed effects models, adjusting for biologically relevant covariates. Results: Epigenetic GA (Bohlin clock) strongly predicted chronological GA (r=0.80, p<0.001) while the Horvath and skin & blood epigenetic age estimates were moderately correlated with chronological age in childhood (Horvath early childhood r=0.48, mid-childhood r=0.43; skin & blood early childhood r=0.68, mid-childhood r=0.56; p<0.001). Higher prenatal As was associated with greater Bohlin GA acceleration (B=0.40 days per doubling in concentration, p=0.03), early childhood Horvath EAA (B=0.14 years per doubling in concentration, p=0.03), early childhood Horvath intrinsic EAA (B=0.14, p=0.03), and Horvath intrinsic EAA across ages in longitudinal analyses (B=0.07, p=0.02). We also observed associations between prenatal Cs and early childhood Horvath EAA (B=0.41, p=0.04) and Horvath intrinsic EAA (B=0.41, p=0.03). Conclusions: Prenatal As and Cs are associated with epigenetic biomarkers of accelerated aging, particularly for those independent of age-related immune changes or intrinsic aging, at birth and in childhood. Future studies may provide insight to the relationship between EAA and health in early life.