Evaluation of the causal effects of perfluorooctanesulfonate on COVID-19 and its associated mechanisms: Integrated Mendelian randomization and network toxicology analyses

Abstract

Observational reports have suggested that exposure to perfluorooctanesulfonate (PFOS) can influence COVID-19 infection-related parameters. This study thus sought to use integrated Mendelian randomization (MR) and network toxicology approaches to clarify the potential causal link between PFOS exposure and COVID-19 severity and the molecular mechanisms underlying this relationship. Inverse-variance-weighted analyses highlighted a causal link between plasma PFOS concentrations and a greater risk of sCOVID-19 (OR 1.293, 95 % CI 1.077–1.552, p = 0.006), but not of SARS-CoV-2 infection (p = 0.257) or COVID-19 hospitalization (p = 0.516). No causal link between PFOS concentration and sCOVID-19 was found by reverse MR. In total, 65 targets were tentatively linked to the relationship between PFOS exposure and sCOVID-19. GO and KEGG analyses highlighted involvement in pathways associated with kinase activity, inflammatory responses, and epithelial and endothelial cell migration. In molecular docking analyses, PFOS was confirmed to readily bind to all five analyzed core targets (IL10, ALB, NOTCH1, PPARG, and NFE2L2). These results suggest that PFOS exposure is causally linked to sCOVID-19 risk, while also offering promising insights into the mechanisms that may underlie this association and candidate targets for treatments aimed at limiting the negative effects of PFOS on COVID-19 severity.