Multi-scale evidence chain: Linking environmental BPA exposure to ovarian cancer through integrated omics and experimental models

BACKGROUND: Ovarian cancer (OC) is a leading cause of female cancer mortality. Beyond genetic and reproductive risk factors, emerging evidence suggests bisphenol A (BPA), a widespread endocrine-disrupting chemical, may contribute to ovarian carcinogenesis, though underlying mechanisms remain unclear. METHODS: We employed a multi-dimensional approach combining: (1) cross-sectional NHANES analysis (66 OC cases, 291 matched controls), (2) two-sample Mendelian randomization using GWAS data, (3) integrative bioinformatics (target prediction, nine GEO datasets, WGCNA, machine learning), (4) molecular docking/dynamics simulations, and (5) functional assays in SKOV3 cells. RESULTS: Urinary BPA levels were significantly elevated in OC patients (p < 0.05).Mendelian randomization suggested a positive association consistent with a potential causal effect (OR=1.25, p = 0.029). Five hub genes (LCN2, LIPA, NR3C1, NR3C2, PGR) were identified across algorithms, showing stable BPA binding in simulations. Single-cell analysis revealed enriched signatures in malignant epithelial cells (p = 0.009). Functional assays confirmed BPA promoted OC proliferation, migration, and invasion (p < 0.05). CONCLUSION: This integrated analysis provides multi-omic evidence supporting an association between BPA exposure and OC pathogenesis, with MR findings suggesting a potential causal relationship that requires independent replication, identifying five hub genes as potential biomarkers and therapeutic targets.