Effect of titanium dioxide nanoparticle on proliferation, drug-sensitivity, inflammation, and metabolomic profiling of human oral cells

Although titanium dioxide nanoparticles (TiO₂ NPs) improve mechanical and antibacterial properties of conventional glass ionomer cements (GIC), their biocompatibility is still controversial. Most of the previous studies of TiO₂ NP toxicity have been done using animal models or nonoral tissue cells. We initiated a series of studies to show how TiO₂ NPs affect viability, inflammation, and drug sensitivity in human malignant and nonmalignant cells derived from the oral cavity. TiO₂ NPs did not affect the cytotoxicity of representative anticancer drugs (doxorubicin, melphalan, 5-FU, docetaxel, gefitinib) against squamous carcinoma cell lines, but significantly stimulated PGE₂ production and COX-1/COX-2 protein expression by gingival fibroblasts in synergy with interleukin-1β (IL-1β). TiO₂ NPs slightly stimulated the proliferation of gingival fibroblasts (possibly for repair synthesis), and also enhanced GIC-induced PGE₂ production, suggesting a possible link between inflammation and hormesis. TiO₂ NPs, once endocytosed into vacuoles, reduced cellular intermediate molecules of the urea cycle and polyamine, S-adenosylmethionine, and glutathione synthetic pathways. TiO₂ NPs further enhanced the IL-1β effects on cellular metabolites. Based on these experimental evidences, we recommend that dental materials containing TiO₂ NPs for patients with gingivitis or periodontitis should be used carefully. Metabolomics analysis may be useful to elucidate the mechanism of inflammation induction and explore the therapeutic strategy for gingivitis and periodontitis.