Per- and polyfluoroalkyl substances exposure and endometriosis risk: Evidence from epidemiologic, network toxicology, and molecular docking

Although per- and polyfluoroalkyl substances (PFAS) exposure has been linked to endometriosis, this association remains controversial, and the underlying mechanisms are unclear. This study aimed to investigate this relationship and explore its molecular basis. Using cross-sectional data from NHANES, we analyzed serum PFAS in 1,069 women (20-50 years), applying WQS and BKMR models to assess mixture effects. Network toxicology (protein-protein interaction, pathway enrichment), molecular docking, and external validation were also used. Results showed PFAS mixtures were positively associated with endometriosis (adjusted OR = 1.22, 95% CI: 1.08-1.39), with PFOA and PFOS as main contributors. Mechanistic analysis revealed 129 overlapping genes involved in steroid hormone signaling, inflammatory responses, and the PI3K-Akt pathway, along with potential disruptions in lipid metabolism and oxidative stress. This work provides epidemiological and mechanistic evidence that PFAS mixtures may promote endometriosis via endocrine disruption and inflammatory activation, highlighting the need for further research into their gynecological health effects.