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Network toxicology and single-cell analysis reveal key gene-mediated bisphenol a interference with granulosa cell function in polycystic ovary syndrome

Yan Zhang,Yuan Lin,Xiumei Xiong,Xiujuan Chen,Xiaoqing Liu,Hailong Huang

Published 2026 in Frontiers in Pharmacology

ABSTRACT

Bisphenol A (BPA), a typical endocrine-disrupting chemical, is implicated in the pathogenesis of Polycystic Ovary Syndrome (PCOS); however, the underlying molecular mechanisms and pathophysiological processes remain unclear. This study aims to decipher molecular interactions between BPA and PCOS-related genetic networks, and to determine the combinatorial impacts of environmental pollutants on PCOS progression. We first identified overlapping genes associated with bisphenol A (BPA) exposure and polycystic ovary syndrome (PCOS) using the Comparative Toxicogenomics Database (CTD). Differentially expressed genes (DEGs) were extracted from three Gene Expression Omnibus (GEO) datasets, while oxidative stress- and apoptosis-related genes were retrieved from the GeneCards database. Subsequently, a series of in silico analyses were performed, including protein-protein interaction (PPI) network construction, functional enrichment profiling, Gene Set Enrichment Analysis (GSEA), immune infiltration evaluation, nomogram development, CB-DOCK molecular docking, and single-cell RNA-seq analysis of the mouse ovarian dataset GSE268919 (DHEA-induced PCOS-like model) to provide cell-type-resolved evidence. Finally, in vitro validation was conducted using primary granulosa cells from PCOS patients and healthy controls, as well as KGN cells, to assess hub gene expression. Functional evaluations were carried out via CCK-8 assay, flow cytometry, quantitative polymerase chain reaction (qPCR), and Western blotting. We identified 139 hub genes between BPA exposure and PCOS, with enrichment in hormone metabolism, ovarian steroidogenesis, and reproductive signaling pathways—among which the apoptotic pathway was prominently associated with these hub genes, indicating BPA exerts a profound impact on cell survival in PCOS. Five hub genes (PTAFR, RACGAP1, CYP19A1, FSHR, DMD) were pinpointed, and a nomogram integrating these genes showed robust PCOS predictive accuracy. Single-gene GSEA further linked the hub genes to immune modulation, inflammation, and cell apoptosis—validating their functional relevance to apoptotic processes in PCOS. Immune cell infiltration analysis revealed discrepancies between PCOS and control groups, with hub genes correlating with specific immune subsets (e.g., pro-inflammatory cells) that may exacerbate apoptotic signaling in ovarian tissues. Molecular docking demonstrated strong binding affinity between BPA and the protein products of hub genes, suggesting direct BPA-mediated interference with their roles in regulating cell apoptosis. In the mouse ovarian scRNA-seq dataset (GSE268919), we observed cell-type-specific dysregulation of Cyp19a1 and Dmd (mouse gene symbols), with stress/apoptosis signatures enriched in specific ovarian cell populations, thereby providing supportive cell-type localization for the hub-gene–associated phenotypes. In vitro validation confirmed dysregulated expression of hub genes in PCOS primary granulosa cells; BPA treatment dose-dependently regulated hub gene expression, inhibited KGN cell proliferation, and significantly induced granulosa cell apoptosis. BPA exposure disrupts granulosa cell survival in PCOS by driving apoptosis-related molecular reprogramming through key gene regulation, thereby elucidating mechanistic links between environmental pollutants and PCOS progression and highlighting potential molecular targets for intervention.

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