J Biomed Nanotechnol. 2020 May 1;16(5):616-625. doi: 10.1166/jbn.2020.2921.
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-/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 (+75-fold to +2.38-fold), Wnt3 (+12% to +135%), Wnt4 (1.33-fold to 6-fold), NF-B (+3.13% to +34.38%), TGF-1 (+1307-fold to +1.85-fold), TGF-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), -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 (-3.12% to -46.88%) and -catenin (-19.57% to -45.65%). These results indicate that hepatic fibrosis induced by nano-TiO₂ is mediated by the TGF-/Smads/MAPK/Wnt signaling pathway. This study provides insight into the mechanism underlying hepatic toxicity induced by nano-TiO₂ .
二氧化钛（TiO₂）和纳米二氧化钛（nano-TiO₂）被广泛应用于食品生产，可能对人体有害。长期暴露于纳米 TiO₂ 可导致肝损伤；然而，纳米 TiO₂ 对肝纤维化的影响及其潜在机制尚不清楚。TGF-/Smad/MAPK/Wnt 信号通路对于组织纤维化非常重要。在本研究中，通过连续 9 个月给小鼠喂食纳米 TiO₂（2.5、5 和 10mg/kg 体重），来研究其对肝纤维化的影响。结果发现纳米 TiO₂ 可诱导肝炎性细胞浸润和肝纤维化，并上调 HIF-1（+75 倍至+2.38 倍）、Wnt3（+12%至+135%）、Wnt4（1.33 倍至 6 倍）、NF-B（+3.13%至+34.38%）、TGF-1（+1307 倍至+1.85 倍）、TGF-1R（+0.8 倍至 1.33 倍）、Smad-2（+0.58 倍至+1.58 倍）、ILK（+0.43 倍至+1.19 倍）、ECM（+1.82 倍至 2.36 倍）、钙蛋白酶 2（+0.11 倍至+0.78 倍）、-SMA（+0.63 倍至+1.56 倍）、c-Myc（+0.27 倍至+0.46 倍）和胶原 I（+8%至+36%）的表达，并增加炎性和纤维性肝组织中 p38MAPK 的磷酸化水平（+66.67%至+153.33%），同时下调 cyclin D（-6.25%至-43.75%）和 GSK-3（-3.12%至-46.88%）及 -catenin（-19.57%至-45.65%）的磷酸化水平。这些结果表明，纳米 TiO₂ 诱导的肝纤维化是通过 TGF-/Smads/MAPK/Wnt 信号通路介导的。本研究为纳米 TiO₂ 诱导肝毒性的机制提供了新的见解。
