Liver Inflammation and Fibrosis Induced by Long-Term Exposure to Nano Titanium Dioxide (TiO₂) Nanoparticles in Mice and Its Molecular Mechanism

Abstract

Titanium dioxide (TiO₂) and nano-sized titanium dioxide (nano-TiO₂), which are used in food production, may be harmful to the body. Long-term exposure to nano-TiO₂ can lead to hepatic injury; however, the effect of nano-TiO₂ on liver fibrosis and the underlying mechanism remain unclear. The TGF-<i>β</i>/Smad/MAPK/Wnt signaling pathway is important for tissue fibrosis. In this study, mice were fed nano-TiO₂ (2.5, 5, and 10 mg/kg body weight) for nine consecutive months to investigate its effect on liver fibrosis. Nano-TiO₂ induced hepatic inflammatory cell infiltration and hepatic fibrosis and upregulated the expression of HIF-1<i>α</i> (+75-fold to +2.38-fold), Wnt3 (+12% to +135%), Wnt4 (1.33-fold to 6-fold), NF-<i>κ</i>B (+3.13% to +34.38%), TGF-<i>β</i>1 (+1307-fold to +1.85-fold), TGF-<i>β</i>1R (+0.8-fold to 1.33-fold), Smad-2 (+0.58-fold to +1.58-fold), ILK (+0.43-fold to +1.19-fold), ECM (+1.82-fold to 2.36-fold), calpain 2 (+0.11-fold to +0.78-fold), <i>α</i>-SMA (+0.63-fold to +1.56-fold), c-Myc (+0.27-fold to +0.46-fold), and collagen I (+8% to +36%), and increased the phosphorylation level of p38MAPK (+66.67% to +153.33%) in inflammatory and fibrotic liver tissues, whereas it downregulated cyclin D (-6.25% to -43.75%) and decreased the phosphorylation levels of GSK-3<i>β</i> (-3.12% to -46.88%) and <i>β</i>-catenin (-19.57% to -45.65%). These results indicate that hepatic fibrosis induced by nano-TiO₂ is mediated by the TGF-<i>β</i>/Smads/MAPK/Wnt signaling pathway. This study provides insight into the mechanism underlying hepatic toxicity induced by nano-TiO₂ .