Environmental bisphenols hijack the Hmox1 and Cdh1 to trigger premature ovarian insufficiency: A multi-omics investigation

BACKGROUND: Bisphenols A (BPA), bisphenols F (BPF), and bisphenols S (BPS) are environmental endocrine disruptors linked to premature ovarian insufficiency (POI), but their molecular targets and pathogenic pathways are not fully understood. The goal of this work was to identify important targets and pathways that contribute to bisphenols-induced POI. METHODS: This study integrated multi-omics approaches. Initially, the toxicological profiles of BPA, BPF, and BPS were assessed, identifying shared targets with POI across multiple databases. Subsequently, based on the construction of a protein-protein interaction network, core biomarkers were refined from the training set using a triple-algorithm machine learning pipeline and further validated for expression stability in the GSE39501 validation set. The biological functions, molecular regulatory mechanisms, and binding affinities were extensively explored through GO/KEGG enrichment analyses, ceRNA networks, and molecular docking. Finally, Single-cell RNA sequencing data (GSE200612) were utilized to characterize ovarian cell heterogeneity and precisely pinpoint key dysregulated cell populations. RESULTS: 8 shared targets were found to be considerably enriched in pathways related to endocrine resistance and apoptotic regulation. Machine learning identified Bcl2, Pparg, Hmox1, and Cdh1 as key targets, with Hmox1 and Cdh1 exhibiting consistent dysregulation in POI models. Strong bisphenol-protein binding was found by molecular docking, particularly for BPF-HMOX1 (ΔG=-7.5 kcal/mol). Single-cell analysis revealed Hmox1 and Cdh1 modification unique to stromal and endothelial cells. CONCLUSIONS: Hmox1 and Cdh1 are pivotal biomarkers for bisphenol-induced POI, modulating apoptosis and endocrine resistance. These targets offer novel therapeutic avenues for environmental toxin-related ovarian dysfunction.