Research On The Cytotoxicity And Immunotoxicity Of Nano Titanium Dioxide

With the rapid development of nano-technology, low toxicity inorganic nanomaterials have been commonly applied in many fields, such as food, medicine, cosmetics, etc. Increasing evidences suggest that nanomaterials pose potential risks to human health. Nowadays, considerable efforts have been devoted to identify the potential toxicity of titanium dioxide nanoparticles（nano-TiO₂）, as a typical low toxicity inorganic namomaterials to cells and organisms. However, reports on the toxicity of different types of nanomaterials still remain conflicting and lack of systematic comparison and analysis. Besides, interactions between nanomaterials and the immune system are also unavoidable. Concerns about the possibility of nanomaterials-mediated immunomodulation promote a growing need to evaluate the effects of these novel materials. This article systematically discussed the toxicological effects and mechanism of nano-TiO₂, and the effect of TiO₂-NRs on the immune function.On one hand, we discussed the toxicological effects and mechanism of nano-TiO₂. The cytotoxicity was considered by two aspects, including nanomaterials on the cell surface and inside the cells. Besides, the mechanism of toxicological effects, such as hindering ion exchange and disrupting exocytosis processes by excess nanomaterials on the cell surface was also concluded. To study the mechanisms, we studied the effect of nano-TiO₂ deposition films on the ions concentration on a simulating the cell membrane. The results showed that the concentration of K+, Ca2+, Na+, Mg2+ and SO42- decreased significantly after filtration through these deposition films. Especifically, at high nano-TiO₂ concentration（200 mg/L） and long nano-TiO₂ deposition time（48 h）, the concentration of Na+ decreased from 2958.01 to 2775.72, 2749.86, 2757.36 and 2719.82 mg/L, respectively, for the four types of nano-TiO₂ in this studied. Similarly, the concentration of SO42- decreased from 38.83 to 35.00, 35.80, 35.40 and 35.27 mg/L, respectively. Adsorption of ions on nano-TiO₂ and the hydrated shell around the ions strongly hindered the ions through the deposition films. The endocytosed nano-TiO₂ could be released from the cells without inducing cytotoxicity and disrupting the normal physiological activities. Hindering the ion exchange and disrupting the exocytosis process is the main factor that induces cytotoxicity in the presence of excess nano-TiO₂ existing on the cell surface.On the other hand, we studied the effect of TiO₂-NRs on the immune function and explore the possibility of TiO₂-NRs to be used in the immune therapy. Based on our results, TiO₂-NRs show specific immunemodulatory effects on the main immune cells. Even at a low concentration of 10 mg/L, TiO₂-NRs can markedly enhance immune responses and stimulate immune cells to release more cytokines. The influence of time and concentration on different cytokines are different. TNF-α and IL-2 which play key role in the antitumor process are upregulated more significantly than that of any other cytokines（IL-4, IL-10 and IFN-γ） in the main immune cells. In the group treated with the high dose of TiO₂-NRs（50 mg/L） for 12 h, the TNF-α content was 530.4 pg/m L compared with 238.2 pg/m L in the saline, the TNF-α content increased to 2.2 times and 4.9 times for macrophages and lymphocytes, respectively. The real time PCR results further confirm the immunemodulatory effects of TiO₂-NRs. Based on our results, we inferred that TiO₂-NRs exposure may trigger T-cell proliferation and bias toward a Th1 immune response and cause a long-lasting activation of lymphocytes involved in adaptive immunity rather than an innate immunity in BALB/c mice. Further, we explore the possibility of TiO₂-NRs to be used in the immune therapy.Herein, we conclude that hindering the ion exchange and disrupting the exocytosis process is the main factor that induces cytotoxicity in the presence of excess nano-TiO₂ existing on the cell surface. Besides, TiO₂-NRs can markedly enhance immune responses and stimulate immune cells to release more cytokines. The current findings may offer a universal principle for understanding the mechanism of cytotoxicity induced by low toxicity nanomaterials. In addition, the study of nano-TiO₂ on immune function has significant importance on the human health and further biological applications.