Work

Investigating the associations of blood lead and cadmium with smoking-related DNA methylation and mortality among U.S. adults

Year: 2025

Type: article

Abstract: PURPOSE: Lead and cadmium have been linked to alterations in DNA methylation (DNAm) and increased mortality. However, the role of smoking-related DNAm in the link between these heavy metals and mortality remains unclear. APPROACH AND RESULTS: We analyzed data from 2110 participants aged 50 and older from the 1999-2002 National Health and Nutrition Examination Survey (NHANES), linked to mortality data from the National Center for Health Statistics (NCHS) with follow-up through 2019. Our study examined the associations between blood lead and cadmium levels, DNA methylation-predicted pack years of smoking (DNAmPackYrs), and mortality outcomes. Our analysis found that higher natural logarithm (Ln)-transformed lead and cadmium levels were positively associated with ln-DNAmPackYrs, with a percent change of 11.34 % (P = 0.001) for lead and 35.57 % (P < 0.001) for cadmium. Participants with both heavy metals above the 50th percentile had the highest DNAmPackYrs, with P for trend < 0.001. Weighted Cox regression analysis demonstrated both ln-lead and ln-DNAmPackYrs were linked to an elevated risk of all mortality outcomes, while ln-cadmium specifically predicted all-cause mortality. A significant interaction between lead and cadmium in relation to all-cause mortality was observed (P for interaction = 0.036). Additionally, significant interactions between DNAmPackYrs and both heavy metals were found in relation to all-cause mortality (P for interaction = 0.001 for lead; P for interaction = 0.013 for cadmium). CONCLUSIONS: Drawing from a nationally representative cohort of older U.S. adults, this study provides robust evidence linking blood lead and cadmium levels to smoking-related DNAm and increased mortality risk. Moreover, the analysis revealed additive effects of these metals on smoking-related DNAm, as well as synergistic impacts on all-cause mortality. Additionally, smoking-induced DNAm may play a role in mediating the connection between heavy metal exposure and mortality risk. Additional research is required to investigate the underlying mechanisms of these associations.

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2025.118360

Authors: Yu-Wei Fang, Ching-Way Chen, Ta-Chen Su, Chikang Wang, Chien-Yu Lin