Arsenic exposure at birth, socioeconomic status, and epigenetic aging among adults in northern Chile

Background: Arsenic exposure remains a major global health concern, and early-life exposure has been linked to cancer, cardiovascular disease, and diabetes. Epigenetic biomarkers of aging may capture long-term effects of arsenic, yet whether exposure during sensitive developmental windows leaves detectable epigenetic signatures decades later remains unclear. Socioeconomic status (SES) may modify these relationships, yet its role as a modifier has not been examined. Methods: We leveraged a natural experiment in northern Chile, where municipal drinking-water arsenic concentrations were extremely high from 1958 to 1972. Decades later, leukocyte DNA methylation was measured among 358 adults (mean age = 65.7 years) using the Illumina EPIC v2 array. Arsenic concentration at birth (0-860 μg/L) was assigned from historical water records. Current exposure was measured in urine (2-646 μg/g creatinine). We evaluated associations of birth and current arsenic exposure with epigenome-wide methylation and epigenetic aging, incorporating multiplicative interaction and stratification by SES. Results: No CpGs were linked to birth arsenic exposure, whereas nine CpGs passed the Bonferroni threshold for current urinary arsenic (p_Bonferroni<0.05). Each doubling of arsenic at birth was associated with older epigenetic age (Hannum: b = 0.11, 95% CI = 0.0027, 0.23; Zhang: b = 0.03, 95% CI = 0.00070, 0.06). SES modified associations for phenotypic age (PC-PhenoAge) and pace of aging (DunedinPACE) (p_interaction<0.05), especially among lower-SES individuals (PC-PhenoAge: b = 0.16, 95% CI = 0.02, 0.29; DunedinPACE: b = 0.0035, 95% CI = 0.00016, 0.0069). Conclusion: Early-life arsenic exposure was associated with accelerated epigenetic aging in adulthood, whereas current exposure was associated with CpG-specific methylation changes, particularly among socioeconomically disadvantaged individuals.