Unveiling the potential targets and mechanisms of DEHP/BPA exposure on PCOS: insights from network toxicology and molecular docking.

Polycystic ovary syndrome (PCOS), a leading cause of infertility in reproductive-aged women, exhibits complex etiology involving environmental endocrine disruptors (EEDs). Di(2-ethylhexyl) phthalate (DEHP) and bisphenol A (BPA) are implicated in PCOS pathogenesis, though their molecular mechanisms remain incompletely characterized. To address this, network toxicology was employed to systematically investigate DEHP/BPA-induced toxicity and associated mechanisms in PCOS. Through comprehensive queries of public databases-including the U.S. Environmental Protection Agency (EPA) ToxCast, Comparative Toxicogenomics Database (CTD), SwissTargetPrediction, GeneCards, and Online Mendelian Inheritance in Man (OMIM)-we identified 26 and 21 putative targets for DEHP/BPA, respectively, with established links to PCOS. Subsequent protein-protein interaction (PPI) network analysis using STRING (v11.0) and Cytoscape (v3.9) identified six hub proteins: PTGER3, SOX15, TOP2A, CCNB1, BCL2, and CYP19A1. Functional enrichment analysis via ClusterProfiler package (version 4.14.6) revealed these targets are significantly enriched in endocrine disruption pathways and ovarian folliculogenesis processes. Molecular docking simulations further validated high-affinity binding between DEHP/BPA and the hub proteins indicating stable interactions. Our results suggest that DEHP/BPA may contribute to PCOS through potential disruption of endocrine signaling, alterations in ovarian hormone regulation, and interference with follicular development and steroidogenesis. These disturbances are predictive of hormonal imbalances, inflammation, and reduced ovarian function, which represent established features of PCOS pathogenesis. The network toxicology approach provides insights into toxicity pathways and could assist in managing risks associated with endocrine-disrupting substances.