The Association of Environmental Toxicants Exposure with Cardiovascular Disease Risk: A Comprehensive Analysis from Population to Molecular Mechanism.

BACKGROUND:Prior studies on toxicants and CVD focused on limited compounds, restricting their relevance to real-world exposure scenarios, a comprehensive assessment multiple toxicants is therefore warranted. METHODS:An exposome-wide association study (ExWAS) was conducted using 61 toxicants in 10 categories among 3577 participants from the 2013-2016 NHANES. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were applied to identify dominant contributors. Mediation analysis and network toxicology were used to explore the mediating roles of the systemic inflammatory response index (SIRI) and phenotypic age acceleration. RESULTS:ExWAS identified 29 toxicants from eight chemical families positively associated with CVD risk. WQS regression revealed that mixed exposures to toxicant family of nicotine metabolites (aOR = 1.45, 95 % CI: 1.18-1.78), metals (aOR = 2.16, 95 % CI: 1.35-3.45), polycyclic aromatic hydrocarbons (PAHs) (aOR = 1.34, 95 % CI: 1.07-1.69), perchlorate/nitrate/thiocyanate (aOR = 1.26, 95 % CI: 1.03-1.53), and volatile organic compound metabolites (VOCs) (aOR = 1.33, 95 % CI: 1.03-1.73) were significantly associated with CVD risk, and BKMR results indicated that metals showed the highest posterior inclusion probability (1.000), followed by PAHs (0.655) and VOCs (0.591). Mediation analysis revealed that SIRI and phenotypic age acceleration significantly mediated the associations of 21 and 18 toxicants with CVD, respectively. Network toxicology analysis demonstrated that toxicants were enriched in multiple inflammaging-related pathways. CONCLUSION:When multiple toxicants are considered simultaneously, the metals, PAHs, and VOCs families contribute most substantially to CVD risk, and inflammaging emerged as mediator of the associations.