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

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.