Examining the Relationships Between Blood Cadmium, DNA Methylation Biomarker, Telomere Length, and Their Associations with Mortality in U.S. Adults

Cadmium exposure has been associated with shortened telomeres, alterations in DNA methylation patterns, and increased mortality. However, the role of DNA methylation in mediating the relationship between cadmium and telomere dynamics is still unclear. Additionally, it is unknow how telomere dynamics and DNA methylation alterations may affect the association between cadmium exposure and mortality outcomes. We utilized data from 8716 National Health and Nutrition Examination Survey (NHANES) participants aged 18 and above, collected between 1999 and 2002, and linked these to mortality outcomes from the National Center for Health Statistics (NCHS) through 2019. In the final model, ln-blood cadmium was significantly and inversely associated with ln-T/S ratio (β = -0.043, 95% CI: -0.059 to -0.027, <i>p</i> < 0.001), while ln-Horvath DNAmTL was strongly and positively associated with ln-T/S ratio (β = 1.782, 95% CI: 1.467 to 2.097, <i>p</i> < 0.001). Moreover, ln-blood cadmium also showed a significant inverse association with ln-Horvath DNAmTL (β = -0.010, 95% CI: -0.014 to -0.006, <i>p</i> < 0.001). Structural equation modeling showed that the association between cadmium and T/S ratio was mediated by Horvath DNAmTL, with a total effect of -0.044, a direct effect of -0.027, and an indirect effect of -0.017. Furthermore, stratified analyses revealed that a 1-unit increase in ln-blood cadmium was associated with higher all-cause mortality, with hazard ratios (HR) of 1.47 for participants with T/S ratio below the median and 1.41 for those above. Similar patterns were observed for cardiovascular (HR = 1.68 vs. 1.30) and cancer mortality (HR = 1.75 vs. 1.42). For Horvath DNAmTL, the association was significant only for all-cause mortality (HR = 1.36 vs. 1.31). However, no significant interactions were detected. In conclusion, our findings suggest that Horvath DNAmTL is associated with the relationship between cadmium and telomere length, suggesting a potential DNA methylation pathway that warrants further longitudinal investigation. Individuals with lower T/S ratios or Horvath DNAmTL appear to be more susceptible to cadmium-related mortality. Further research is necessary to confirm these results.