Network Toxicology and Molecular Dynamics Simulation Elucidate Bisphenol A-Induced Neurotoxicity in SVGP12 Astrocytes: Mechanistic Insights and Risk Assessment for Chronic Neurodegenerative Diseases
Bisphenol A (BPA), a high-volume industrial chemical, is implicated in neurotoxicity and chronic neurodegenerative diseases. This study integrates network toxicology, molecular docking, and molecular dynamics simulations to systematically delineate the common mechanisms linking BPA to Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Using the human astrocyte cell line SVGP12 as an in vitro model, we identified six key toxic functional proteins—TP53, HSP90AA1, HSP90AB1, INS, BCL2, and AKT1—that mediate BPA's effects across these diseases, with BCL2 emerging as the most central node. Experimental validation demonstrated that BPA induces oxidative stress and cell cycle arrest, suppresses the INS-AKT1-BCL2 anti-apoptotic pathway, and activates the TP53-HSP90 pro-apoptotic pathway, culminating in mitochondrial apoptosis of astrocytes and disruption of neural microenvironment homeostasis. These findings reveal a convergent mechanism by which BPA accelerates neurodegeneration, filling a critical gap in understanding BPA's role in AD, PD, and HD. The study provides a novel theoretical framework and experimental evidence for BPA neurotoxicity risk assessment and informs preventive and therapeutic strategies for BPA-related neurodegenerative disorders.