Shared and compound-specific pathways of bisphenol A and its analogues in male infertility: An integrative approach combining network toxicology, omics analysis, and molecular docking.

This study aimed to elucidate the potential mechanisms by which common bisphenols (BPs) contribute to male infertility. Five representative BPs (BPA, BPS, BPF, BPAF, TBBPA) were analyzed using an integrated strategy combining network toxicology, omics analysis (via GEO and TCGA datasets), literature review and molecular docking. Predicted BP targets from SwissTargetPrediction and TargetNet were intersected with male infertility-related genes from GeneCards. Overlapping targets underwent protein-protein interaction (PPI) network construction and enrichment analysis. Core target expression was analyzed using GEO and TCGA databases and literature review. Core targets were docked with BPs, followed by 100 ns MD simulations and MM/PBSA binding free energy decomposition. Eleven potential common targets were identified, which were enriched in the apoptotic signaling pathway, mitochondrial membrane permeability regulation, and steroid hormone biosynthesis. Four core targets-PTGS2, BCL2, AR, and CYP19A1-showed high connectivity. TCGA analysis demonstrated significant downregulation of PTGS2 and CYP19A1 in seminoma. Literature evidence showed consistent BCL2 suppression across BPs, AR inhibition by BPA, BPS, and TBBPA, CYP19A1 upregulation by BPA and BPAF, and PTGS2 upregulation by BPA. TBBPA-PTGS2 and BPA-AR complexes exhibited the strongest and most stable binding, dominated by van der Waals forces, whereas the BPAF-CYP19A1 complex showed strong electrostatic attraction, offset by polar solvation. BPs may impair male fertility through shared BCL2-mediated apoptosis, with computational evidence suggesting compound-specific pathways involving CYP19A1 (steroidogenesis), AR (androgen signaling), and PTGS2 (inflammation). These findings underscore the need for compound-specific toxicological assessments integrating mechanistic and computational evidence to guide precise prevention and regulatory strategies.