基于网络毒理学、分子对接技术探讨双酚A 对尿道下裂的作用机制

Investigating the Mechanism of Bisphenol A in Hypospadias Based on Network Toxicology and Molecular Docking

摘要: 目的：探索双酚A (Bisphenol A, BPA)毒性机制对防治尿道下裂的意义。方法：采用网络毒理学结合分子对接技术，通过PubChem、ChEMBL、GeneCards等数据库筛选BPA的作用靶点及尿道下裂相关靶点，利用韦恩图分析交集基因。构建蛋白质–蛋白质相互作用网络筛选核心靶点，并通过基因本体论和京都基因与基因组百科全书富集分析揭示通路机制。最后，利用AutoDock进行分子对接验证核心靶点与BPA的结合模式。结果：共筛选出36个BPA诱导尿道下裂的潜在靶点，其中ESR1、PPARG为核心靶点(结合能分别为−6.84 kcal/mol、−8.10 kcal/mol)。富集分析表明BPA通过内分泌抵抗、雌激素信号通路、MAPK信号通路、PI3K-AKT信号通路调控尿道下裂进程。分子对接证实BPA与核心靶点通过氢键和疏水作用稳定结合。结论：通过网络毒理学为BPA诱导尿道下裂的分子机制提供初步见解，ESR1和PPARG可能在BPA诱导尿道下裂中发挥关键作用，为环境毒物与疾病关联的机制探索提供新的方法学参考。

Abstract: Objective: To explore the significance of bisphenol A toxicity mechanisms for the prevention and treatment of hypospadias. Methods: Network toxicology and molecular docking techniques were used. Targets of BPA action and hypospadias-related targets were screened through databases such as PubChem, ChEMBL, and GeneCards. Intersecting genes were analyzed using a Venn diagram. A protein-protein interaction network was constructed to screen core targets, and the pathway mechanisms were elucidated through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Finally, AutoDock was used for molecular docking to verify the binding modes between core targets and BPA. Results: A total of 36 potential targets for BPA-induced hypospadias were screened, with ESR1 and PPARG identified as core targets (binding energies of −6.84 kcal/mol and −8.10 kcal/mol, respectively). Enrichment analysis indicated that BPA regulates the progression of hypospadias through endocrine resistance, the estrogen signaling pathway, the MAPK signaling pathway, and the PI3K-AKT signaling pathway. Molecular docking confirmed that BPA stably binds to the core targets via hydrogen bonds and hydrophobic interactions. Conclusion: This study, using network toxicology, provides preliminary insights into the molecular mechanisms of BPA-induced hypospadias. ESR1 and PPARG may play key roles in BPA-induced hypospadias, offering a new methodological reference for exploring the mechanisms linking environmental toxins and diseases.