环境与职业医学2024，Vol.41Issue(12)：1361-1368,8.DOI:10.11836/JEOM24387
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
摘要
Abstract
[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 new-borns.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 Tox-icogenomics 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 pheno-types,for further understanding the relevant gene-molecule interaction toxicity pathway net-work.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 path-way involved in PFAS-related RB development,based on KEGG and a priori knowledge.The acti-vation 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 demon-strated good binding affinity with most RTKs,with chlorinated polyfluorinated ether sulfonates(Cl-PFESAs)showing particularly favorable predicted 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 toxicological mechanism linking PFAS to an increased risk of RB.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Key words
per-and polyfluoroalkyl substances/retinoblastoma/adverse outcome pathway/PI3K-AKT/MAPK signaling pathway分类
医药卫生引用本文复制引用
桂玉燕,王廷极,王铭昊,徐亚棋,张蕴晖..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[J].环境与职业医学,2024,41(12):1361-1368,8.基金项目
国家重点研发计划项目(2022YFC2705004) （2022YFC2705004）
