Environmental Chemical-Induced Cardiometabolic Disorders: Combined Epidemiological and Experimental Evidence

Screening environmental pollutants that are harmful to the cardiometabolic status and understanding their key toxic pathways are crucial for effective clinical intervention. Based on exposure data of 46 chemicals in a nationally representative 13,286 people, logistic regression and mixture modeling were used to preliminarily identify environmental pollutants with significant impacts on 12 indicators for cardiometabolic disorders. A total of 15 chemicals were found to be associated with the integrated latent class, among which four chemicals (perfluorononanoic acid [PFNA], perfluorooctanoic acid [PFOA], thiocyanate, and thallium) also contributed significantly to the mixture effect. We constructed the adverse outcome pathways (AOPs) for nine significant toxicants in both models of individual chemicals and the mixture for each cardiometabolic disorder. Notably, fluoroalkyl substances affect multiple aspects of hyperlipidemia by activating PPARα. We performed molecular docking and <i>in vitro</i> experiments to verify and supplement the toxicological mechanism of PFNA. Through binding to PPARα, PFNA increased the levels of downstream molecules including CD36 (fatty acid transfer), ACSL1 (fatty acid activation), and CPT1a (intracellular transfer for β-oxidation) and ultimately promoted the accumulation of triglycerides and lipid droplets in HepG2 cells. These markers, together with key events for other metabolic phenotypes, may be potential targets for scientific research or clinical treatment.