Evidence of epigenetic age acceleration among adults with prenatal and early life arsenic exposure in Northern Chile

Background: Prenatal arsenic exposure influences epigenetic programming. The long-term influence on epigenetic age acceleration (EAA), a biomarker of morbidity and mortality, is unknown. We tested associations between prenatal and early-life arsenic exposure and epigenetic age acceleration in adulthood. Methods: Peripheral blood mononuclear cells (PBMCs) and buccal cells were collected from adults with high prenatal and early-life arsenic exposure (median = 555 μg/L in drinking water) and adults never exposed in Northern Chile (N = 40, age range: 44-53 years). Six measures of epigenetic age and EAA were calculated (Horvath age, Hannum age, PhenoAge, skin and blood age, GrimAge, and DNA methylation telomere length). Associations between high arsenic exposure or estimated water arsenic concentrations at birth and EAA were evaluated using linear models adjusted for sex and smoking. Results: In PBMCs, chronological age was strongly correlated with all epigenetic clocks (rPearson = 0.62-0.86) and DNA methylation telomere length (rPearson = -0.69); in buccal cells, correlations were significant but weaker. On average, adults with prenatal and early-life arsenic exposure had six-year greater PhenoAge acceleration in PBMCs [B (95% CI) = 6.01 (2.60, 9.42); adjusting for average lifetime water arsenic concentrations in adulthood: B (95% CI) = 6.65 (1.91, 11.38)]. Associations with Hannum EAA [B (95% CI) = 2.51 (-0.81, 5.83)] and extrinsic EAA [B (95% CI) = 3.66 (-0.91, 8.23)] in PBMCs, and with PhenoAge acceleration [B (95% CI) = 4.88 (-1.60, 11.36)] in buccal cells were positive but statistically significant. Associations with arsenic concentrations at birth were similar; PBMC PhenoAge increased by 0.32 (95% CI: 0.003, 0.63) years for each doubling in arsenic concentrations. Conclusions: This study suggests that arsenic exposure limited to early-life stages is associated with accelerated epigenetic aging in adulthood, particularly biomarkers developed to predict morbidity and mortality. EAA might serve as a risk biomarker of early-life exposures.