Inhibition of Epithelial-Mesenchymal Transition and Tissue Regeneration by Waterborne Titanium Dioxide Nanoparticles.

Titanium dioxide nanoparticles (TiO2NPs) are among the most widely manufactured nanomaterials with broad applications in food industry, cosmetics, and medicine. Although the toxicity of TiO2NPs at high doses has been extensively explored, the potential health risks of TiO2NPs 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 TiO2NPs inhibits EMT-mediated cell remodeling and cell migration without exhibiting cytotoxicity. Further investigation reveals that TiO2NPs suppress the process of EMT through the blockade of transforming growth factor-β (TGFβ) signaling. Particularly, TiO2NPs 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 TiO2NPs do not elicit toxicity in healthy tissues but hamper EMT-mediated wound healing in two animal models. Long-term exposure of TiO2NPs 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 TiO2NPs during tissue remodeling and repair, which have significant implications in their risk assessment and management.