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<p>Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical (EDC), disrupts hormonal signaling and induces inflammation, yet its role in osteoarthritis (OA) pathogenesis remains unclear, underscoring a critical environmental health research gap. We employed network toxicology and molecular docking techniques to analyze BPA’s interactions with OA-associated protein targets. Key genes were identified through multi-database integration and prioritized using topological metrics (degree/betweenness/closeness centrality). Enrichment analysis (GO/KEGG) was conducted to map biological pathways. At the same time, AutoDock Vina evaluated the binding affinities of three compounds (BPA, the OA treatment drug abiraterone retrieved from DrugBank, and the OA modeling agent iodoacetic acid) with core targets. Integrated analysis identified 233 shared BPA-OA targets. Enrichment analysis revealed that BPA perturbs extracellular matrix (ECM) organization (<i>p</i> = 3.2 × 10⁻<sup>5</sup>), activates NF-κB and MAPK signaling pathways (<i>p</i> &lt; 0.001), and alters arachidonic acid metabolism. Molecular docking demonstrated that among five key targets (COL1A1, CYP2C19, ITGB1, PTGS2, and TP53), BPA exhibited its strongest binding toward CYP2C19 (–7.3&#xa0;kcal/mol), surpassing iodoacetic acid (–3.5&#xa0;kcal/mol) and showing comparable affinity to the therapeutic drug abiraterone (–10.1&#xa0;kcal/mol). Based on this result, the BPA-CYP2C19 complex was selected for subsequent molecular dynamics simulations, which confirmed remarkable conformational stability, sustained hydrogen-bond interactions, and favorable binding free-energy contributions over a 100-ns trajectory. Furthermore, ProTox-3.0 predicted the oral LD₅₀ of BPA in rats to be 4950&#xa0;mg/kg (toxicity class 5), indicating relatively low acute oral toxicity. Collectively, these findings highlight CYP2C19 as the preferential target of BPA, provide mechanistic insights into its OA-related toxicity, and support its translational toxicological evaluation. This study provides a new theoretical framework for understanding the mechanism of action of BPA in OA, emphasizing the role of network toxicology in exacerbating OA. These findings may inform future research on the risk of exposure to DEP and provide important insights for public health policy and the development of targeted therapeutic strategies.</p>

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Bisphenol A disrupts cartilage homeostasis through CYP2C19

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月5日

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  • Yichen Bai,
  • Kai Feng,
  • Tengyao Niu,
  • Xu Bai,
  • Zhirong Chen

摘要

Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical (EDC), disrupts hormonal signaling and induces inflammation, yet its role in osteoarthritis (OA) pathogenesis remains unclear, underscoring a critical environmental health research gap. We employed network toxicology and molecular docking techniques to analyze BPA’s interactions with OA-associated protein targets. Key genes were identified through multi-database integration and prioritized using topological metrics (degree/betweenness/closeness centrality). Enrichment analysis (GO/KEGG) was conducted to map biological pathways. At the same time, AutoDock Vina evaluated the binding affinities of three compounds (BPA, the OA treatment drug abiraterone retrieved from DrugBank, and the OA modeling agent iodoacetic acid) with core targets. Integrated analysis identified 233 shared BPA-OA targets. Enrichment analysis revealed that BPA perturbs extracellular matrix (ECM) organization (p = 3.2 × 10⁻5), activates NF-κB and MAPK signaling pathways (p < 0.001), and alters arachidonic acid metabolism. Molecular docking demonstrated that among five key targets (COL1A1, CYP2C19, ITGB1, PTGS2, and TP53), BPA exhibited its strongest binding toward CYP2C19 (–7.3 kcal/mol), surpassing iodoacetic acid (–3.5 kcal/mol) and showing comparable affinity to the therapeutic drug abiraterone (–10.1 kcal/mol). Based on this result, the BPA-CYP2C19 complex was selected for subsequent molecular dynamics simulations, which confirmed remarkable conformational stability, sustained hydrogen-bond interactions, and favorable binding free-energy contributions over a 100-ns trajectory. Furthermore, ProTox-3.0 predicted the oral LD₅₀ of BPA in rats to be 4950 mg/kg (toxicity class 5), indicating relatively low acute oral toxicity. Collectively, these findings highlight CYP2C19 as the preferential target of BPA, provide mechanistic insights into its OA-related toxicity, and support its translational toxicological evaluation. This study provides a new theoretical framework for understanding the mechanism of action of BPA in OA, emphasizing the role of network toxicology in exacerbating OA. These findings may inform future research on the risk of exposure to DEP and provide important insights for public health policy and the development of targeted therapeutic strategies.