Integrated in silico analysis for the identification of key genes and signaling pathways in copper oxide nanoparticles toxicity

Abstract

Copper oxide nanoparticles (CuO-NPs) are used in various industrial and commercial products due to their enhanced physicochemical properties. The vast consumption increases their exposure in the environment, thereby affecting the ecosystem. Even with the rise in research towards understanding their toxicity, the major signaling cascades and key genes involved in CuO-NPs remain elusive due to the various attributes involved (size, shape, charge, coating in terms of nanoparticles, and dose, duration, and species used in the experiment). The focus of the study is to identify the key signaling cascades and genes involved in CuO-NPs toxicity irrespective of these attributes. CuO-NPs related microarray expression profiles were screened from GEO database and were subjected to toxicogenomic analysis to elucidate the toxicity mechanism. In silico tools were used to obtain the DEGs, followed by GO and KEGG functional enrichment analysis. The identified DEGs were then analyzed to determine major signaling pathways and key genes. Module and centrality parameter analysis was performed to identify the key genes. Further, the miRNAs and transcription factors involved in regulating the genes were predicted, and their interactive pathways were constructed. A total of 44 DEGs were commonly present in all the analysed datasets and all of them were downregulated. GO analysis reveals that most of the genes were enriched in functions related to cell division and chemotaxis. Cell-cycle, chemokine, cytokine-cytokine receptor interaction, and p53 signaling pathways were the key pathways with Cdk1 as the major biomarker altered irrespective of the variables (dosage, duration, species used, and surface coating). Overall, our integrated toxicogenomic analysis reveal that Cdk1 regulated cell cycle and cytokine-cytokine signaling cascades might be responsible for CuO-NPs toxicity. These findings will help us in understanding the mechanisms involved in NPs toxicity.

Keywords: Cell cycle; Copper oxide nanoparticles; Cytokines; Nanotoxicity; Toxicogenomics.