Concentration-dependent toxicogenomic changes of silver nanoparticles in hepatocyte-like cells derived from human induced pluripotent stem cells

Abstract

The application of silver nanoparticles (AgNPs) in consumer products has been increasing rapidly over the past decades. Therefore, in vitro models capable of accurately predicting the toxicity of AgNPs are much needed. Hepatocyte-like cells (HLCs) derived from human induced pluripotent stem cells (iPSCs) represent an attractive alternative in vitro hepatotoxicity model. Yet, the use of iPSC-derived HLCs (iPSC-HLCs) for the study of nanoparticle toxicity has not been reported so far. In the present study, transcriptomic changes induced by varying concentrations (5-25 mu g/ml) of AgNPs were characterized in iPSC-HLCs after 24-h exposure. AgNPs caused concentration-dependent gene expression changes in iPSC-HLCs. At all the concentrations, members of the metallothionein (MT) and the heat shock protein (HSP) families were the dominating upregulated genes, suggesting that exposure to AgNPs induced oxidative stresses in iPSC-HLCs and as a result elicited cellular protective responses in the cells. Functional analysis showed that the differentially expressed genes (DEGs) were majorly involved in the biological processes of metabolism, response to stress, and cell organization and biogenesis. Ingenuity Pathway Analysis revealed that cancer was at the top of diseases and disorders associated with the DEGs at all concentrations. These results were in accordance with those reported previously on hepatoma cell lines and primary hepatocytes. Considering the advantages iPSC-HLCs have over other liver cell models in terms of unlimited supply, consistency in quality, sustainability of function in long-term culture, and, more importantly, affordability of donor specificity, the results of the current study suggest that iPSC-HLCs may serve as a better in vitro model for liver nanotoxicology.