Association between mixed urinary metal exposure and metabolic syndrome in the population of Guangxi, China: Mechanistic insights from a case-control study

Exposure to metals has been associated with metabolic syndrome (MetS), yet the combined effects of multiple metals and their underlying molecular mechanisms remain unclear. This study aimed to investigate the associations between urinary metal levels and the risk of MetS and its components, and further explored potential mechanistic pathways. Data were obtained from 11,115 participants in the Guangxi Ethnic Minority Cohort Study of Chronic Diseases (2018-2019). Logistic regression, restricted cubic splines (RCS), Bayesian Kernel Machine Regression (BKMR), and generalized Weighted Quantile Sum (gWQS) models were applied to assess both individual and combined effects of 22 urinary metals on MetS and its components. Mechanistic insights were explored using the Comparative Toxicogenomics Database (CTD) and functional enrichment analyses, while mediation analysis was performed to identify MetS components that may act as intermediaries in the metal-MetS pathway. Our findings indicated that Mn, Cu, Zn, Pb, and Sb exposure was positively associated with MetS risk, whereas Mg, Ti, Rb, and Tl levels were inversely associated(P < 0.05). Both BKMR and gWQS models consistently revealed that combined exposure to metal mixtures increased the risk of MetS and its clinical components, with Zn and Mn identified as major contributors. Mechanistically, these metal mixtures may promote MetS development through pathways involving oxidative stress, metabolic dysregulation, vascular injury and adipose accumulation, with EGF, SOD1, HMGCR, VEGFA, CCL2, and ABCB1 serving as pivotal regulatory genes. At the clinical phenotype level, mediation analysis suggested that central obesity and reduced HDL-C were key mediators in the metal-MetS association. Collectively, this study provides novel epidemiological and mechanistic evidence linking mixed metal exposure to MetS, underscoring the need for enhanced environmental monitoring and public health interventions to mitigate the growing MetS burden.