Toxicity of Zirconia oxide Nanoparticles: Liver Biodistribution and Liver Damages

Abstract Background: Zirconia nanoparticles (ZrO2-NPs) have been increasingly used in industrial, biomedical and dental materials. However, the scientific basis for the toxicological effects of ZrO2-NPs is poorly elucidated, and the understanding of the underlying mechanism is still limited. Results: The hepatic biodistribution and toxicological effects of ZrO2-NPs after intravenous administration (20mg/kg bw) in vivo and the toxicological mechanism toward hepatocytes in vitro were investigated. The liver showed continuous ZrO2-NP accumulations liver over a 28-d period. Moreover, ZrO2-NPs induced oxidative stress and increased inflammatory responses and functional injury in the liver. Hepasteatosis and cell death were observed in histopathological and immunohistochemical studies. RNA-seq identified the main pathways involved in the metabolism, cellular process, and human diseases. The RT-qPCR analysis results showed that ZrO2-NP exposure caused the upregulation of P53, Foxo1, Gadd45g, P21, Caspase3, and PPARα and the downregulation of Igfbp2 and Akt in the liver in response to the ZrO2-NP treatment. Meanwhile, the results of the in vitro studies demonstrated that ZrO2-NPs exposure resulted in cytotoxicity in Hepg2 cells in a dose- and time-dependent manner. ZrO2-NPs were proven to induce oxidative stress, lipid accumulation, cell cycle arrest and cell apoptosis to Hepg2 cells. Western-blot analysis further proved the depression of Igfbp2, activation of Akt-mediated signaling pathway and P53-mediated signaling pathway for Hepg2 cells exposure to ZrO2-NPs. Conclusions: This study proves that ZrO2-NPs have negative impacts on the liver and exhibit potential risks for non-alcoholic fatty liver disease (NAFLD). There is potential concern over ZrO2-NPs' hepatoxicity in biomedical applications and occupational exposure through large-scale production.