Multi-scale analysis reveals key targets mediating BPA-induced sensorineural hearing loss

The mechanism of bisphenol A (BPA) on sensorineural hearing loss (SNHL) remains undefined. This study investigates BPA's toxic mechanism on SNHL. ProTox database was performed to analyze the toxicity of BPA. Intersection genes were screened using network toxicology, and causal genes associated with SNHL were identified through Mendelian randomization. The ligand-protein binding activity was validated through molecular docking and dynamic simulation. BPA showed a toxicity classification of Class 4, with toxicological profiles involving the blood-brain barrier, mitochondrial membrane potential, and estrogen receptor alpha. A total of 92 BPA target genes were found to be related to SNHL. These were enriched in potassium ion channel processes and MAPK, PI3K-Akt pathways. Two-sample Mendelian randomization identified 3 causal genes, with small effect sizes: MANBA (odds ratios [OR] = 0.950, P = .009), PDE6D (OR = 1.055, P = .001), vascular endothelial growth factor A (OR = 1.030, P = .022). Molecular docking with BPA revealed minimum binding free energies of -8.1, -6.7, and -6.1 kcal/mol; MANBA-BPA binding was stable in dynamics simulations. BPA can exert toxic effects on SNHL through potassium channel related processes, as well as MAPK and PI3K-Akt signaling pathways. MANBA, PDE6D, and vascular endothelial growth factor A also play key mediating roles in this process.