Associations of Heavy Metals with Activities of Daily Living Disability: An Epigenome-Wide View of DNA Methylation and Mediation Analysis

BACKGROUND: Exposure to heavy metals has been reported to be associated with multiple diseases. However, direct associations and potential mechanisms of heavy metals with physical disability remain unclear. OBJECTIVES: We aimed to quantify associations of heavy metals with physical disability and further explore the potential mechanisms of DNA methylation on the genome scale. METHODS: A cross-sectional study of 4,391 older adults was conducted and activities of daily living (ADL) disability were identified using a 14-item scale questionnaire including basic and instrumental activities to assess the presence of disability (yes or no) rated on a scale of dependence. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated to quantify associations between heavy metals and ADL disability prevalence using multivariate logistic regression and Bayesian kernel machine regression (BKMR) models. Whole blood–derived DNA methylation was measured using the HumanMethylationEPIC BeadChip array. An ADL disability-related epigenome-wide DNA methylation association study (EWAS) was performed among 212 sex-matched ADL disability cases and controls, and mediation analysis was further applied to explore potential mediators of DNA methylation. RESULTS: Each 1-standard deviation (SD) higher difference in [Formula: see text]-transformed manganese, copper, arsenic, and cadmium level was significantly associated with a 14% (95% CI: 1.05, 1.24), 16% (95% CI:1.07, 1.26), 22% (95% CI:1.13, 1.33), and 15% (95% CI:1.06, 1.26) higher odds of ADL disability, which remained significant in the multiple-metal and BKMR models. A total of 85 differential DNA methylation sites were identified to be associated with ADL disability prevalence, among which methylation level at cg220000984 and cg23012519 (annotated to IRGM and PKP3) mediated 31.0% and 31.2% of manganese-associated ADL disability prevalence, cg06723863 (annotated to ESRP2) mediated 32.4% of copper-associated ADL disability prevalence, cg24433124 (nearest to IER3) mediated 15.8% of arsenic-associated ADL disability prevalence, and cg07905190 and cg17485717 (annotated to FREM1 and TCP11L1) mediated 21.5% and 30.5% of cadmium-associated ADL disability prevalence (all [Formula: see text]). DISCUSSION: Our findings suggested that heavy metals contributed to higher prevalence of ADL disability and that locus-specific DNA methylation are partial mediators, providing potential biomarkers for further cellular mechanism studies. https://doi.org/10.1289/EHP10602