基于PI3K-AKT/MAPK为关键事件构建PFAS-视网膜母细胞瘤有害结局路径  

Constructing adverse outcome pathway for per-and polyfluoroalkyl substances and retinoblastoma based on PI3K-AKT/MAPK signaling pathway

作　　者：桂玉燕 王廷极 王铭昊 徐亚棋 张蕴晖[1] GUI Yuyan;WANG Tingji;WANG Minghao;XU Yaqi;ZHANG Yunhui(School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education,Fudan University,Shanghai 200032)

机构地区：[1]复旦大学公共卫生学院/公共卫生安全教育部重点实验室,上海200032

出　　处：《环境与职业医学》2024年第12期1361-1368,共8页Journal of Environmental and Occupational Medicine

基　　金：国家重点研发计划项目(2022YFC2705004)。

摘　　要：[背景]全氟和多氟烷基物质(PFAS)暴露与多种癌症相关,近期研究发现亦可能增加新生儿罹患视网膜母细胞瘤(RB)的风险,然而致病机制尚不明确。[目的]通过构建基于公共数据库的PFAS-RB有害结局路径(AOP)框架,以阐明PFAS与RB之间关联的潜在机制。[方法]通过比较毒理基因组学数据库获取化合物与疾病互作基因,经京都基因与基因组百科全书(KEGG)富集分析与先验知识确定关键毒性扰动通路。R语言软件的“Pathview”包进一步分析预测分子起始事件、关键事件及其相关表型,绘制基因-分子的互作毒性通路网络图。分子对接技术验证PFAS与上游受体亲和力。借鉴经典AOP构建方法,构建了一个以毒性通路为核心的AOP框架。[结果]通过KEGG富集分析结合已有的先验知识,确定PI3K-AKT/MAPK信号通路作为PFAS诱导RB发生过程中的潜在毒性通路。受体酪氨酸激酶(RTKs)激活为分子起始事件,关键分子原癌基因如RAS和AKT以及核因子κB(NF-κB)活化,抑癌基因P53被抑制。本研究中测算的14种PFAS与大多数RTKs间具有良好的结合活性;其中,氯代多氟醚磺酸盐(Cl-PFESAs)与各个受体间的对接结合能较低,预测的分子对接结果较好;与恶性肿瘤密切相关的原癌基因酪氨酸蛋白激酶、表皮生长因子受体以及神经营养性酪氨酸激酶受体1为预测分子对接结果最好的受体。[结论]PI3K-AKT/MAPK信号通路可能是PFAS作为RB高危因素的潜在毒理学机制。[Background]Exposure to per-and polyfluoroalkyl substances(PFAS)is associated with various cancers,and recent studies suggest it may also increase the risk of retinoblastoma(RB)in newborns.However,the pathogenic mechanisms remain unclear.[Objective]By constructing an adverse outcome pathway(AOP)framework based on public databases to elucidate the potential mechanisms linking PFAS and RB.[Methods]Chemical-gene interactions and disease-gene interactions from the Comparative Toxicogenomics Database were retracted to identify key toxicological disruption pathways using Kyoto Encyclopedia of Genes and Genomes(KEGG)and a priori knowledge.The Pathview package in R was employed to predict molecular initiating events,key events,and their associated phenotypes,for further understanding the relevant gene-molecule interaction toxicity pathway network.Molecular docking techniques were utilized to validate the affinity of PFAS for these molecular initiating events.An AOP framework focused on toxicological pathways was developed using classical AOP methodologies.[Results]The PI3K-AKT/MAPK signaling pathway was identified as a potential toxicological pathway involved in PFAS-related RB development,based on KEGG and a priori knowledge.The activation of receptor tyrosine kinases(RTKs)served as the molecular initiating event,leading to the activation of key oncogenes such as RAS and AKT,as well as nuclear factor kappa-light chain enhancer of activated B cells (NF-κB), along with the inhibition of the tumor suppressor gene P53. In this study, 14 types of PFAS demonstratedgood binding affinity with most RTKs, with chlorinated polyfluorinated ether sulfonates (Cl-PFESAs) showing particularly favorablepredicted binding. Oncogenes, including the c-kit-encoded tyrosine kinase receptor for stem cell factor, epidermal growth factor receptor,and neurotrophic tyrosine kinase receptor 1, were identified as the receptors with the best predicted binding affinity.[Conclusion] The PI3K-AKT/MAPK signaling pathway may serve as a potential toxicolo

关 键 词：全氟和多氟烷基物质 视网膜母细胞瘤 有害结局路径 PI3K-AKT/MAPK信号通路 

分 类 号：R114[医药卫生—卫生毒理学]