Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences , Shanghai 200031, China.
School of Public Health, Guangzhou Medical University , Guangdong 511436, China.
ACS Appl Mater Interfaces. 2018 Jan 31;10(4):3449-3458. doi: 10.1021/acsami.7b18986. Epub 2018 Jan 18.
Titanium dioxide nanoparticles (TiONPs) are among the most widely manufactured nanomaterials with broad applications in food industry, cosmetics, and medicine. Although the toxicity of TiONPs at high doses has been extensively explored, the potential health risks of TiONPs exposure at nontoxic concentrations remain poorly understood. Epithelial-mesenchymal transition (EMT) plays pivotal roles in a diversity of physiological and pathological processes, including tissue regeneration and cancer metastasis. In this study, we find that the cellular uptake of TiONPs inhibits EMT-mediated cell remodeling and cell migration without exhibiting cytotoxicity. Further investigation reveals that TiONPs suppress the process of EMT through the blockade of transforming growth factor-β (TGFβ) signaling. Particularly, TiONPs interact with the TGFβ receptor TβRI/II complex, induce its lysosomal degradation, and thereby downregulate expression of TGFβ target genes. Moreover, we show that waterborne TiONPs do not elicit toxicity in healthy tissues but hamper EMT-mediated wound healing in two animal models. Long-term exposure of TiONPs in environmental water and drinking water impede the regeneration of amputated fin in zebrafish and the recovery of intestinal mucosal damage in colitic mice. Our results reveal the previously unknown effects of TiONPs during tissue remodeling and repair, which have significant implications in their risk assessment and management.
二氧化钛纳米颗粒（TiONPs）是应用最广泛的纳米材料之一，广泛应用于食品工业、化妆品和医药领域。尽管高剂量 TiONPs 的毒性已得到广泛研究，但在非毒性浓度下 TiONPs 暴露的潜在健康风险仍知之甚少。上皮-间充质转化（EMT）在多种生理和病理过程中发挥着关键作用，包括组织再生和癌症转移。在本研究中，我们发现 TiONPs 的细胞摄取抑制了 EMT 介导的细胞重塑和细胞迁移，而没有表现出细胞毒性。进一步的研究表明，TiONPs 通过阻断转化生长因子-β（TGFβ）信号通路来抑制 EMT 过程。具体来说，TiONPs 与 TGFβ 受体 TβRI/II 复合物相互作用，诱导其溶酶体降解，从而下调 TGFβ 靶基因的表达。此外，我们还表明，水基 TiONPs 在健康组织中不会引起毒性，但会阻碍两种动物模型中 EMT 介导的伤口愈合。环境水中和饮用水中的长期 TiONPs 暴露会阻碍斑马鱼断鳍的再生和结肠炎小鼠肠道黏膜损伤的恢复。我们的研究结果揭示了 TiONPs 在组织重塑和修复过程中的未知作用，这对其风险评估和管理具有重要意义。
