Exploring the mechanism of plastic additives on reproductive disorders based on network toxicology and molecular docking

Abstract Phthalate esters (PAEs) and organophosphate esters (OPEs) are pervasive 20 environmental pollutants with endocrine-disrupting properties. Despite growing 21 evidence linking PAE/OPE exposure to female reproductive disorders, the 22 diseasespecific molecular targets and cross-disease mechanistic convergence in 23 polycystic ovary syndrome (PCOS), recurrent pregnancy loss (RPL), and 24 endometriosis remain undefined. We employed an integrative network toxicology 25 framework combining molecular docking, network pharmacology, multi-omics 26 analysis to systematically elucidate PAE/OPE-target interactions across three 27 clinically interrelated reproductive disorders. Our analysis identified disease-specific28 hub genes, ESR1 and MMP9 for PCOS, CTNNB1 and BCL2 for RPL, and IL6 and 29 NFKB1 for endometriosis, along with shared pathogenic mechanisms including 30 NF-κB activation, PI3K-AKT dysregulation, and microRNA-mediated regulation. 31 Molecular docking confirmed direct binding of DEHP, MEHP, and TPHP to key hub32 targets. Diagnostic nomograms integrating hub genes achieved AUCs of 0.72–0.94, 33 suggesting their potential as biomarkers for risk stratification. This study provides a 34 cross-disease network framework linking PAE/OPE exposure to female reproductive35 toxicity, offering mechanistic insights and candidate biomarkers for risk assessment 36 and targeted prevention strategies. Disclosure statement No potential conflict of interest was reported by author(s). Data availability statement The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.