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