Potential Biomarkers and Drugs for Nanoparticle-Induced Cytotoxicity in the Retina: Based on Regulation of Inflammatory and Apoptotic Genes

The eye is a superficial organ directly exposed to the surrounding environment. Thus, the toxicity of nanoparticle (NP) pollutants to the eye may be potentially severer relative to inner organs and needs to be monitored. However, the cytotoxic mechanisms of NPs on the eyes remain rarely reported. This study was to screen crucial genes associated with NPs-induced retinal injuries. The gene expression profiles in the retina induced by NPs [GSE49371: Au20, Au100, Si20, Si100; GSE49048: presumptive therapeutic concentration (PTC) TiO2, 10PTC TiO2] and commonly used retinal cell injury models (optic nerve injury procedure: GSE55228, GSE120257 and GSE131486; hypoxia exposure: GSE173233, GSE151610, GSE135844; H2O2 exposure: GSE122270) were obtained from the Gene Expression Omnibus database. A total of 381 differentially expressed genes (including 372 mRNAs and 9 lncRNAs) were shared between NP exposure and the optic nerve injury model when they were compared with their corresponding controls. Function enrichment analysis of these overlapped genes showed that Tlr2, Crhbp, Ccl2, Cxcl10, Fas, Irf8, Socs3, Stat3, Gbp6, Casp1 and Syk were involved in inflammatory- and apoptotic-related processes. Protein-protein interaction network analysis revealed eight of them (Tlr2, Ccl2, Cxcl10, Irf8, Socs3, Stat3, Casp1 and Syk) were hub genes. Moreover, Socs3 could interact with upstream Stat3 and downstream Fas/Casp1/Ccl2/Cxcl10; Irf8 could interact with upstream Tlr2, Syk and downstream Cxcl10. Competing endogenous RNAs network analysis identified Socs3, Irf8, Gdf6 and Crhbp could be regulated by lncRNAs and miRNAs (9330175E14Rik-mmu-miR-762-Socs3, 6430562O15Rik-mmu-miR-207-Irf8, Gm9866-mmu-miR-669b-5p-Gdf6, 4933406C10Rik-mmu-miR-9-5p-Crhbp). CMap-CTD database analyses indicated the expression levels of Tlr2, Ccl2, Cxcl10, Fas, Irf8, Socs3, Stat3, Gbp6, Casp1 and Syk could be reversed by folic acid. Crhbp and Gdf6 were also verified to be downregulated, while Tlr2, Ccl2, Irf8, Socs3 and Stat3 were upregulated in hypoxia/H2O2-induced retinal injury models. Hereby, our findings suggest that Crhbp, Irf8, Socs3 and Gdf6 as well as their upstream mRNAs, lncRNAs and miRNAs may be potential monitoring biomarkers and therapeutic targets for NP-induced retinal injuries. Folic acid supplementation may be a preventive and therapeutic approach.