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

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 remain unclear. Socioeconomic status (SES) may modify these relationships, yet its role as a modifier has not been examined. We leveraged a natural experiment in northern Chile, where municipal drinking-water arsenic concentrations were extremely high from 1958-1972. 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 (0-860μg/L) was assigned from historical water records. Current exposure was measured in urine (2-646μg/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. 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: 0.03, 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). 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. • Higher arsenic at birth was linked to accelerated epigenetic aging decades later. • Epigenetic aging linked to arsenic at birth was evident in lower socioeconomic status. • Current arsenic exposure was associated with widespread CpG methylation changes. • Social disadvantage shaped epigenetic responses to arsenic across the life course.