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

TL;DR

This study finds that exposure to certain chemicals called PFAS may increase the risk of endometriosis by disrupting hormones and causing inflammation.

Contribution

The study combines epidemiological data with network toxicology and molecular docking to reveal potential mechanisms linking PFAS to endometriosis.

Findings

PFAS mixtures were positively associated with endometriosis, with PFOA and PFOS as key contributors.

129 overlapping genes were identified in pathways related to hormone signaling, inflammation, and the PI3K-Akt pathway.

Molecular docking suggests PFAS bind to core targets, supporting endocrine disruption as a mechanism.

Abstract

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.

•NHANES links PFAS mixtures to endometriosis risk; PFOA/PFOS are key drivers•Network analysis finds 129 shared genes in hormone/inflammation/PI3K-Akt pathways•Molecular docking confirms PFAS bind core targets, implicating endocrine disruption•Multi-model approach reveals PFAS mixture synergy, advancing toxicity assessment

NHANES links PFAS mixtures to endometriosis risk; PFOA/PFOS are key drivers

Network analysis finds 129 shared genes in hormone/inflammation/PI3K-Akt pathways

Molecular docking confirms PFAS bind core targets, implicating endocrine disruption

Multi-model approach reveals PFAS mixture synergy, advancing toxicity assessment

Biochemistry; Environmental toxicology; Molecular toxicology

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