What does this research mean for the field?

BPA exposure contributes to granulosa cell dysfunction in polycystic ovary syndrome (PCOS) through an m6A–apoptosis axis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

What question did this study set out to answer?

To explore the relationship between BPA exposure, m6A dysregulation, and apoptosis in granulosa cells related to PCOS.

February 22, 2026Journal of Ovarian Research1 citationsOpen Access

Integrative bioinformatics, single-cell and experimental evidence for a BPA–m6A–apoptosis axis in granulosa cell dysfunction in polycystic ovary syndrome

YZYan ZhangFujian Medical University YLYuan LinFujian Medical University XXXiumei XiongFujian Medical University

Key Points

To explore the relationship between BPA exposure, m6A dysregulation, and apoptosis in granulosa cells related to PCOS.
Retrieved BPA-related genes and intersected with PCOS-related datasets
Conducted protein–protein interaction and enrichment analyses
Developed a five-gene logistic model and nomogram
Utilized single-cell RNA-seq data for hub-gene mapping
Performed molecular docking analyses to evaluate BPA-protein binding
Identified 139 BPA-PCOS shared genes and five hub genes related to granulosa cell function
Achieved an AUC of 0.846 in training and 0.791 in validation for the five-gene nomogram
Observed changes in hub-gene expression linked to m6A and apoptosis in granulosa cells
In vitro studies confirmed BPA reduced cell viability and increased apoptosis through specific pathways
Molecular docking indicated moderate-to-strong binding between BPA and hub proteins.

Abstract

Polycystic ovary syndrome (PCOS) is increasingly viewed as an environmentally influenced, epigenetically mediated reproductive–metabolic disorder. Bisphenol A (BPA) exposure is higher in women with PCOS and has been linked to hyperandrogenism, insulin resistance and ovarian dysfunction, while N6-methyladenosine (m6A) dysregulation contributes to granulosa cells (GCs) proliferation and apoptosis. However, the downstream gene networks that integrate BPA exposure, m6A imbalance and GCs apoptosis in PCOS remain unclear. BPA-related genes were retrieved from the Comparative Toxicogenomics Database and intersected with PCOS differentially expressed genes from four GEO GC datasets (GSE34526, GSE137684, GSE102293, GSE80432) and m6A/apoptosis-related genes from GeneCards. Protein–protein interaction, GO/KEGG enrichment, GSEA and immune-cell infiltration (ssGSEA) analyses were performed. A five-gene logistic model and nomogram were built and externally validated in GSE106724 and GSE98595. Single-cell RNA-seq data (GSE268919) were used to map hub-gene expression, m6A and apoptosis signatures across ovarian cell types. Molecular docking (AutoDock Vina) evaluated BPA–protein binding. Hub-gene expression and function were verified in primary human GCs and BPA-treated KGN cells by qPCR, Western blot, CCK-8 and flow cytometry. We identified 139 BPA–PCOS shared genes and five hub genes—LIFR, LMNA, BCL2, ADM, S100P—enriched in ovarian steroidogenesis, oxidative-stress and apoptotic pathways. These genes showed distinct expression patterns between PCOS and controls and were associated with altered immune-cell infiltration. A five-gene nomogram achieved an AUC of 0.846 in the training set and 0.791 in an external validation cohort, with good calibration and decision-curve benefit. Single-cell analysis revealed LIFR downregulation and LMNA upregulation in GCs clusters with high m6A and apoptosis scores. Docking predicted moderate-to-strong BPA binding to all five proteins. In vitro, BPA reduced GCs viability, increased apoptosis with BAX/Caspase-3 activation, and reproduced the hub-gene dysregulation observed in PCOS GCs. Our integrative data support a BPA–m6A–apoptosis axis in PCOS and identify a five-gene granulosa-cell signature with potential diagnostic utility, providing mechanistic insight and candidate targets for environmentally driven PCOS; however, its clinical utility requires validation in larger, independent and prospectively recruited cohorts. This work is an observational and experimental laboratory study and not a clinical trial.

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