Molecular Mechanisms Of Liver Injury Induced By Titanium Dioxide Nanoparticles

In recent years, due to the rapid development of nanotechnology, more and more nanomaterials are development, utilization, and then used in the production and deep into every aspect of people’s lives. The diameter of nano-titanium dioxide（nano- TiO₂） is below 100 nanometer, its appearance is white loose powder. And it has some properties like anti-UV, anti-bacterial, self-cleaning, anti-aging, so it can be used in all areas of lives, such as cosmetics, food, functional fibers, plastics, inks, coatings, paints, fine ceramics. Because of wide application of nano-TiO₂, people pay more attention on its harmful to human body and environment. Animal experiments show that nano-TiO₂ can enter into the body through respiratory, digestive and other internal transport pathway, even the skin. And then it can through the blood circulation and lymphatic circulation transported to various organs of the body and deposition, induced toxic effects on the body. At present, it rarely knows the specific molecular mechanism that nano- TiO₂ to cause liver dysfunction. In view of this point, the experiments of this paper treated mice with low doses nano-TiO₂（anatase 5 nm） by long-term. We explored the molecular mechanism of liver dysfunction caused by nano-TiO₂ through the change of body weight, body ratio, biochemical indicators and protein expression. This study may provide some important experimental datas for using nano-TiO₂ safety.The main contents of this paper are listed as follows:（1） The mice were exposed to nano-TiO₂（2.5, 5, 10 mg / kg BW） for six consecutive months, and studied the mechanisms of liver injury induced by nano-TiO₂. The results showed a significant reduction in body weight after nano-TiO₂ treated mice, while the mice liver index increased significantly（hepatomegaly）. At the same time, the liver biopsy of experimental mice showed severe pathological changes, such as inflammatory cell infiltration, vascular dilatation, congestion of liver tissue gap, and progressive liver cell necrosis. According to TEM observation, the ultrastructure of liver cells showed obvious apoptosis, including severe mitochondrial swelling, chromatin nuclear membrane disintegration and marginalization. Further, there were some black particle aggregates in the cytoplasm of hepatocytes, mitochondrial, and nuclear membrane in the experimental group. This also proved that nano-TiO₂ could be deposited in the liver cells. With increasing doses of nano-TiO₂, the levels of ALT, AST, ALP, and LDH had gradually increased. This fully illustrates the long-term exposure to nano-TiO₂ led to liver injury. IL-4 and IL-5 expression of Th2 cytokines and Th1-type cytokines IL-12 had a dose-dependent increase in the liver tissue of treated groups. The target gene of IL-4 and IL-12, including IFN-γ, GATA3, GATA4, T-bet, STAT3, STAT6, chemokines, MCP-1, and MIP-2 had significantly increased, and STAT1 showed a significant downward trend. These results show that the nano-TiO₂-induced liver toxicity may be related to activating IL-4-mediated pathway, and Th2 factors may be involved in nano-TiO₂-induced hepatic inflammation.（2） Mice were exposed to titanium dioxide（2.5, 5, 10 mg / kg BW） for 90 consecutive days, we explored the mechanism that JAK-STAT pathway may be involved in hepatic inflammation induced by nano-TiO₂. The expression level of COX, NGAL and ENA-78 gradually increased with the increase of nano-TiO₂ dosage, but PPAR- γ and PGC-1 expression levels were gradually reduced, ET-1 and P2X7 are no significant differences between the four groups, respectively.The expression of JAK2,STAT3 and IL-6 increased by 2.19 %, 20.46 % and 32.7%; 195.52%, 335.72% and 348.19%; 61.67 %, 219.95% and 330.97%; while the expression of SOCS1 decreased 5.2%, 6.67% and 50.05% as compared to the corresponding control group, respectively. These findings showed that the JAK-STAT pathway may be involved in mouse liver damages due to nano-TiO₂ exposure.