Joint effects of per- and polyfluoroalkyl substances and heavy metals on dyslipidemia: Integrated epidemiological and bioinformatics analysis.

Exposure to per- and polyfluoroalkyl substances (PFAS) and heavy metals may be associated with dyslipidemia. However, evidence regarding the joint associations and potential interactions of these pollutants remains limited, and the biological pathways that might be relevant to these associations are not yet fully understood. This study, conducted in three communities in Guangzhou, China involving 1310 participants during 2018 to 2019, investigated the associations between co-exposure to serum PFAS (detection frequency over 85%) and three plasma heavy metals (arsenic (As), lead (Pb), and cadmium (Cd)) with dyslipidemia. Bioinformatic approaches were used to identify candidate biological processes potentially related to these associations. The results showed that individual PFAS, As, and Cd were positively associated with dyslipidemia. Furthermore, the Grouped Weighted Quantile Sum (GWQS) regression model indicated that co-exposure to PFAS and heavy metals was positively associated with dyslipidemia (odds ratio (OR) = 2.19, 95% confidence interval (CI): 1.80, 2.68). Significant additive interaction effect was observed between perfluoro-n-nonaoic acid (PFNA) and Cd for dyslipidemia, with the low-exposure group for both pollutants as reference (relative excess risk due to the interaction (RERI) = 1.21, 95% CI: 0.39, 2.02). A total of 110 overlapping genes associated with PFAS, Cd, and dyslipidemia were identified. KEGG enrichment analyses highlighted PPAR signaling pathway, cholesterol metabolism, insulin resistance, AMPK signaling pathway, and adipocytokine signaling pathway as candidate biological processes shared among PFAS, Cd exposure, and dyslipidemia. Subsequent six hub genes (PPARA, PPARG, APOB, APOE, INS, and SREBF1) were screened using Cytoscape. These findings provide new insights into the associations between multiple pollutants co-exposure with human health and identify potential biological pathways for future mechanistic investigation.