Association of metal and metalloid exposure with cardiovascular-kidney-metabolic syndrome: mediation by inflammation, oxidative stress, and aging.

backgroundMetal and metalloid exposure has been linked to various health impairments; however, its association with Cardiovascular-Kidney-Metabolic (CKM) syndrome has not been systematically investigated. This study aims to evaluate this relationship.

methodsThis cross-sectional study analyzed data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999-2018. Urinary concentrations of nine metal and metalloid species (barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, and tungsten) were examined. Weighted multinomial logistic regression was used to assess associations between individual metals and CKM syndrome stages. Additionally, mixture models including quantile g-computation (Qgcomp), weighted quantile sum (WQS), and Bayesian kernel machine regression (BKMR) were applied to evaluate combined effects of metals and metalloids. Mediation analyses explored whether inflammation, oxidative stress, and biological aging may partially mediate these associations. Subgroup analyses were conducted by sex, age, and race. Sensitivity analyses including urinary arsenic were also conducted (2003-2018 NHANES cycles).

resultsAfter applying exclusion criteria, a total of 6,650 participants were included (3,358 men and 3,292 women; mean age 47.3 years, SD = 16.5). CKM syndrome exhibited a high prevalence in the U.S. POPULATION: Except for lead, higher CKM stages were generally associated with higher urinary metal levels. Multiple statistical models consistently indicated significant positive associations between exposure to several metals and CKM syndrome. Barium, thallium, and antimony were significantly associated with the overall odds of CKM syndrome, as well as with the risks of Stage 1 and Stage 2 CKM, with barium showing the highest weight. For advanced CKM stages, antimony had the greatest contribution, followed by tungsten and cobalt. Significant variations were observed by sex, age, and race. Mediation analyses suggested that inflammation, oxidative stress, and biological aging may partially explain the observed associations between metal co-exposure and CKM syndrome. In the sensitivity analysis, inorganic arsenic showed the strongest positive association with CKM syndrome and contributed most prominently in the mixture models.

conclusionsExposure to metal and metalloid species is closely associated with the prevalence of CKM syndrome at different stages. Inflammation, oxidative stress, and biological aging may play partial mediating roles in these associations. As NHANES reflects exposure patterns in the U.S. general population, the findings are most applicable to community-level environmental exposures and should not be directly extrapolated to high-exposure occupational groups. Further validation in prospective cohort studies and mechanistic research is warranted.