A computational analysis of multi-target mechanisms linking bisphenol A to precocious puberty

Background Bisphenol A (BPA), a widely distributed endocrine-disrupting chemical (EDC), has been associated with altered pubertal timing in children, including precocious puberty (PP). However, the multi-target molecular mechanisms potentially linking BPA exposure to PP remain incompletely understood. Objective To explore the potential multi-target mechanisms by which BPA may contribute to PP using an integrated computational framework. Methods We combined network toxicology, protein–protein interaction (PPI) network analysis, molecular docking, and molecular dynamics (MD) simulations. Shared targets between BPA and PP were identified through database mining, core targets were prioritized by PPI analysis, and functional enrichment, molecular docking, and MD simulations were used to characterize candidate pathways and predicted target interactions. Results We identified 54 shared targets between BPA and PP, including 12 prioritized core targets such as estrogen receptor 1 (ESR1), androgen receptor (AR), insulin (INS), insulin-like growth factor 2 (IGF2), and B-Raf proto-oncogene (BRAF). Functional enrichment analysis indicated that these targets were mainly involved in reproductive developmental processes, nuclear receptor activity, and major signaling pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K-Akt) signaling, cyclic guanosine monophosphate/protein kinase G (cGMP-PKG) signaling, and mitogen-activated protein kinase (MAPK). Molecular docking predicted favorable binding of BPA to selected core targets (binding energies: −3.9 to −9.3 kcal/mol), and MD simulations supported relatively stable complex formation for the AR–BPA, BRAF–BPA, and ESR1–BPA systems (RMSD: 0.25–0.5 Å; MM/GBSA: −27.67 to −34.05 kcal/mol). Overall, these findings suggest that BPA may influence pubertal regulation through interconnected processes involving ESR1/AR-related steroid signaling, INS/IGF2-linked metabolic and epigenetic regulation, and BRAF/MAPK-associated intracellular signaling. Conclusion This study provides a hypothesis-generating computational framework for understanding how BPA may be associated with PP. Our analyses support a putative multi-target model involving ESR1/AR-related steroid signaling, INS/IGF2-linked metabolic and epigenetic regulation, and BRAF/MAPK-associated intracellular signaling. These findings refine the mechanistic map of BPA-associated PP and identify biologically plausible targets for further study. As an in silico analysis, however, these findings should be interpreted cautiously and require further validation in experimental and clinical settings.