DEHP对骨质疏松的毒性影响及分子机制研究  

Study on the toxic effect and molecular mechanism of DEHP on osteoporosis

作　　者：潘娜 黄新周 姜敏[2] 卫永鲲[1] PAN Na;HUANG Xinzhou;JIANG Min;WEI Yongkun(Department of Orthopaedics,Hanzhong 3201 Hospital,Xi’an Jiaotong University,Shaanxi Province,Hanzhong723000,China;School of Chemistry and Environmental Science,Shaanxi University of Technology,Shaanxi Province,Hanzhong723000,China)

机构地区：[1]西安交通大学附属汉中三二〇一医院骨科,陕西汉中723000 [2]陕西理工大学化学与环境科学学院,陕西汉中723000

出　　处：《中国医药导报》2024年第34期5-11,共7页China Medical Herald

基　　金：国家临床重点专科建设项目(陕卫医函〔2023〕325号)。

摘　　要：目的探讨DEHP对骨质疏松的毒性影响及分子机制。方法使用Ch EMBL、STITCH数据库筛选DEHP的潜在作用靶点,下载GEO数据库中的相关数据集获取骨质疏松的靶基因,绘制维恩图获取共同关联基因。通过基因本体论(GO)和京都基因与基因组百科全书(KEGG)富集分析共同关联基因在DEHP诱导的骨质疏松(OP)中的功能与通路。使用随机森林、支持向量机、广义线性和极端梯度提升模型筛选关键基因,构建列线图模型并进行验证。通过Auto Dock进行分子对接,验证DEHP对关键基因的直接影响及作用位点。结果确定了13个交叉靶标可作为DEHP诱导OP的潜在靶点。GO富集分析显示,共同关联基因主要影响对视黄酸受体信号通路、基因表达的昼夜节律调节、有丝分裂细胞周期的正向调节和对T细胞活化的负调控等生物学功能等。KEGG富集分析显示,共同关联基因主要影响类固醇的生物合成、肾素-血管紧张素系统和叶酸的生物合成等。筛选5个关键基因(SQLE、KDM5A、CDC25C、AKR1C3和ENPEP)作为生物标志物并绘制列线图模型。模型校准度高,获益阈值广泛,具有实用价值。5个核心靶蛋白都表现出与DEHP的强结合力,结合能均<-5kcal/mol。结论DEHP可能通过启动肾素-血管紧张素-醛固酮系统途径,影响OP的发生和发展。SQLE、KDM5A、CDC25C、AKR1C3和ENPEP可作为DEHP诱导OP的潜在靶点。Objective To investigate the toxic effect of DEHP on osteoporosis and its molecular mechanism.Methods ChEMBL and STITCH database were used to screen potential targets of DEHP,target genes of osteoporosis were obtained by downloading relevant data sets from GEO database,and co-associated genes were obtained by drawing Venn diagram.The function and pathways of co-associated genes in DEHP-induced osteoporosis(OP)were analyzed by gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.The key genes were screened using random forest,support vector machine,generalized linear,and extreme gradient boosting,and the nomogram model was constructed and verified.Molecular docking was performed by AutoDock to verify the direct effects of DEHP on key genes and the action sites.Results Thirteen crossover targets were identified as potential targets for DEHP-induced OP.GO enrichment analysis showed that co-associated genes mainly affect biological functions such as retinoic acid receptor signaling pathway,circadian regulation of gene expression,positive regulation of mitotic cell cycle,and negative regulation of T cell activation.KEGG enrichment analysis showed that co-associated genes mainly affect steroid biosynthesis,renin-angiotensin system,and folate biosynthesis.Five key genes(SQLE,KDM5A,CDC25C,AKR1C3,and ENPEP)were screened as biomarkers and a nomogram model was drawn.The model had high calibration degree and wide benefit threshold,so it had practical value.All the five core target proteins showed strong binding force with DEHP,with binding energy<-5 kcal/mol.Conclusion DEHP may affect the occurrence and development of OP by activating the renin-angiotensin-aldosterone system pathway.SQLE,KDM5A,CDC25C,AKR1C3,and ENPEP can be used as potential targets for DEHP-induced OP.

关 键 词：DEHP 机器学习 分子对接 骨质疏松 

分 类 号：R681.1[医药卫生—骨科学]