Network toxicology and molecular docking elucidation of oligoasthenospermia induced by bisphenol analogues: a comparative study of BPA, BPS, BPF, and BPAF.

Abstract

Bisphenol A (BPA) substitutes are increasingly prevalent in consumer products, yet their potential to induce oligoasthenospermia (OAS) remains poorly understood. This study combined network toxicology, molecular docking, and 500-ns molecular dynamics (MD) simulations to systematically compare the toxicity mechanisms of BPA, BPS, BPF, and BPAF in the context of OAS. Intersection analysis identified 25 shared targets, with topological clustering highlighting ESR1, AR, CYP19A1, TNF, and IL6 as central hubs linking endocrine disruption with inflammatory pathways. Molecular docking revealed broad receptor engagement (-5.4 to -8.7 kcal/mol), with BPAF exhibiting the strongest affinities, particularly for ESR1 (-8.7 kcal/mol) and CYP19A1 (-8.4 kcal/mol). Molecular Dynamics (MD) simulations confirmed the dynamic stability of the ESR1-BPAF complex, demonstrating a compact fold (SASA ~124 nm²), minimal structural drift (ligand RMSD ~0.16 nm; protein RMSD ~0.20 nm), and persistent hydrogen bonding anchored by residues GLU353 and LEU428. These computational findings predict that BPA alternatives - especially BPAF - may significantly perturb steroidogenic and inflammatory axes to drive spermatogenic impairment. This study provides a predictive hazard prioritization framework that challenges the safety assumption of 'BPA-free' substitutes and warrants urgent experimental validation.