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In an effort to examine signaling pathway of inflammation of the mouse liver caused by intragastric administration of titanium dioxide nanoparticles (NPs), we assessed Toll-like receptor-2 (TLR2), TLR-4, IκB kinase (IKK-α, IKK-β), IκB nucleic factor-κB (NF-κB), NF-κBP52, NF-κBP65, tumor necrosis factor-α (TNF-α), NF-κB-inducible kinase (NIK), interleukin-2 (IL-2), biochemical parameters of liver functions, and histopathological changes and liver ultrastructure in the TiO(2) NPs-treated mice. The results showed the titanium accumulation in liver, histopathological changes and hepatocytes apoptosis of mice liver, and the liver function damaged by TiO(2) NPs. The real-time quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay analyses showed that TiO(2) NPs can significantly increase the mRNA and protein expression of TLR2 and TLR4 and several inflammatory cytokines, including IKK1, IKK2, NF-κB, NF-κBP52, NF-κBP65, TNF-α, and NIK, and TiO(2) NPs can significantly decrease the mRNA and protein expression of IκB and IL-2. The results of this study added to our understanding of TiO(2) NPs-induced liver toxicity. It implied that the signaling pathway of liver injury in the TiO(2) NPs-stimulated mouse liver sequentially might occur via activation of TLRs→NIK→IκB kinase→NF-κB→TNF-α→inflammation→apoptosis→liver injury.

Although it is known that nano-TiO2or other nanoparticles can induce liver toxicities, the mechanisms and the molecular pathogenesis are still unclear. In this study, nano-anatase TiO2(5 nm) was injected into the abdominal cavity of ICR mice for consecutive 14 days, and the inflammatory responses of liver of mice was investigated. The results showed the obvious titanium accumulation in liver DNA, histopathological changes and hepatocytes apoptosis of mice liver, and the liver function damaged by higher doses nano-anatase TiO2. The real-time quantitative RT-PCR and ELISA analyses showed that nano-anatase TiO2can significantly alter the mRNA and protein expressions of several inflammatory cytokines, including nucleic factor-κB, macrophage migration inhibitory factor, tumor necrosis factor-α, interleukin-6, interleukin-1β, cross-reaction protein, interleukin-4, and interleukin-10. Our results also implied that the inflammatory responses and liver injury may be involved in nano-anatase TiO2-induced liver toxicity.

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Nano-TiO2 was shown to cause various toxic effects in both rats and mice; however, the molecular mechanism by which TiO2 exerts its toxicity is poorly understood. In this report, an interaction of nano-anatase TiO2 with liver DNA from ICR mice was systematically studied in vivo using ICP-MS, various spectral methods and gel electrophoresis. We found that the liver weights of the mice treated with higher amounts of nano-anatase TiO2 were significantly increased. Nano-anatase TiO2 could be accumulated in liver DNA by inserting itself into DNA base pairs or binding to DNA nucleotide that bound with three oxygen or nitrogen atoms and two phosphorous atoms of DNA with the Ti–O(N) and Ti–P bond lengths of 1.87 and 2.38 Å, respectively, and alter the conformation of DNA. And gel electrophoresis showed that higher dose of nano-anatase TiO2 could cause liver DNA cleavage in mice.

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