ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Obstetric and Pediatric Pharmacology
Network toxicology and single-cell analysis reveal key gene-mediated bisphenol A interference with granulosa cell function in Polycystic Ovary Syndrome
Provisionally accepted
- Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, China
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Background: Bisphenol A (BPA), a typical endocrine-disrupting chemical, is implicated in the pathogenesis of polycystic ovary syndrome (PCOS), yet the molecular links between BPA-associated networks and granulosa-cell dysfunction remain incompletely defined. We aimed to integrate toxicogenomic and transcriptomic evidence to identify key BPA–PCOS genes and to provide mechanistic clues relevant to granulosa-cell apoptosis. Methods: BPA–PCOS overlapping genes were obtained from the Comparative Toxicogenomics Database. Differentially expressed genes were identified from three Gene Expression Omnibus datasets, and oxidative stress/apoptosis-related genes were retrieved from GeneCards. We performed protein–protein interaction analysis, functional enrichment, single-gene GSEA, immune infiltration estimation, nomogram construction, and CB-DOCK molecular docking. For cell-type context, we analyzed a published mouse ovarian scRNA-seq dataset (GSE268919; DHEA-induced PCOS-like model). Experimental validation was conducted in primary granulosa cells from PCOS patients and controls and in KGN cells using qPCR/Western blotting, CCK-8, and flow cytometry. Results: We identified 139 BPA–PCOS overlapping genes enriched in hormone metabolism, ovarian steroidogenesis, and reproductive signaling, with apoptosis-related programs prominently represented. Five hub genes (PTAFR, RACGAP1, CYP19A1, FSHR, and DMD) were prioritized, and a nomogram based on these genes showed good discriminatory performance for PCOS. Single-gene GSEA linked hub genes to apoptosis- and inflammation/immune-related pathways. Immune infiltration analyses suggested altered immune signatures in PCOS and correlations with hub genes; these findings are association-based predictions from bulk deconvolution. Molecular docking indicated favorable binding of BPA to hub-gene protein products. In mouse ovarian scRNA-seq data, Cyp19a1 and Dmd (mouse gene symbols) displayed cell-type-specific dysregulation, with stress/apoptosis signatures enriched in specific ovarian populations. In vitro, hub genes were dysregulated in PCOS primary granulosa cells; BPA treatment dose-dependently modulated hub-gene expression, inhibited KGN proliferation, and increased granulosa-cell apoptosis. Conclusions: Our integrative analyses identify BPA-associated hub genes linked to granulosa-cell apoptosis in PCOS and provide multi-layered evidence (bioinformatics, mouse single-cell localization, and human granulosa-cell validation) supporting potential molecular targets for further mechanistic and translational studies.
Keywords: diagnostic biomarkers, Endocrine Disruptors, Granulosa cell apoptosis, Network toxicology, Polycystic Ovary Syndrome, single-cell sequencing
Received: 26 Nov 2025; Accepted: 06 Feb 2026.
Copyright: © 2026 Zhang, Lin, Xiong, Chen, Liu and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yan Zhang
Hailong Huang
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