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.

Present and Future of ZrO2 Nanostructure as Reservoir for Drug Loading and Release

“…In the literature was revealed that Zr NPs have better biocompatibility when compared to other metallic nanoparticles [111][112][113], but there are some studies with ZrNPs demerits regarding some toxicity in bioapplications, affecting their safety use which was tested with specific in vitro assays. As an example, the article "Zirconia Nanoparticles-Induced Toxic Effects in Osteoblast-Like 3T3-E1 Cells" is an investigation of Zr NPs nanoparticles with sizes between 81 and 94 nm for a longer time and higher concentrations [114].…”

Effect of Silicone Rubber/Polyvinyl Alcohol /Zirconium Oxide Compound on Mesenchymal Stromal Cells

“…Meanwhile, the results of the in vitro studies demonstrated that ZrO 2 -NPs exposure resulted in cytotoxicity in Hepg2 cells in a dose-and time-dependent manner. RNA-sequence from the spleen and brain of mice injected with ZrO 2 nanoparticles showed significant changes in gene expression (37). Alzahrani et al reported the apoptotic and DNA-damaging effects of Yttria-stabilized ZrO 2 -NPs also known as Yttria Zirconia, Yttria Stabilized Zirconium Oxide, on human skin epithelial cells (38).…”