| In recent years, TiO2 nanoparticles have increasingly been used in the fields of paints, waste water treatment, sterilization, cosmetics, food additive, bio-medical ceramic and implanted biomaterials largely due to its appropriate physicochemical properties. However, it is these unique characteristics such as small sizes, large surface per mass and high reactivity that nanoparticulate anatase TiO2 can enter the human body quickly, and then imposes potential risks on human health. Several studies have reported that nanoparticulate TiO2 could cause biological and toxic effects. But the mechanisms of these effects need to be further study. So we investigated the toxic effects and related mechanisms of various doses of nanoparticulate TiO2 (5 nm) with injection into abdominal cavity of mice everyday for 14 days. And we also studied the mechanism of interaction of nanoparticulate TiO2 and Superoxide dismutase (SOD), which is a kind of important antioxidant enzymes, in vitro. Our results could provide an important theoretical basis for evaluating the nanotoxicity.Three main aspects are involved:(1) The overall toxicity of nanoparticulate TiO2 to mice. The coefficients of organs and serum biochemical parameters were investigated after nanoparticulate TiO2 (5 nm) was injected into the abdominal cavity of ICR mice everyday for 14 days. The results showed that, with increasing doses of nanoparticulate TiO2, the coefficients of liver, kidney and spleen increased gradually, while the coefficients of lung and brain decreased gradually, and the coefficient of heart had little change. The order of the titanium accumulation in the organs was liver> kidneys> spleen>lung>brain>heart. With higher dose of nanoparticulate TiO2 , the indicators of liver function, such as alkaline phosphatase, alanine aminotransferase, leucine-acid peptide, pseudo-cholinesterase, total protein, albumin level were enhanced significantly; the indicators of kidney function, such as uric acid and blood urea nitrogen were decreased; the activities of aspartate aminotransferase, creatine kinase, lactate dehydrogenase and alpha-hydroxybutyrate dehydrogenase, indicator of the myocardium function were increased. The contents of triglycerides, glucose, and high-density lipoprotein cholesterol were significantly elevated. Taken together, nanoparticulate TiO2 in higher dose caused serious damage to the liver, kidney and myocardium of mice, and disturbed the balance of blood sugar and lipid in mice. The accumulation of titanium in the organs might be closely related to the coefficients of organs and the inflammatory responses of mice.(2) The mechanisms and the molecular pathogenesis of acute liver injury in mice caused by nanoparticulate TiO2. In this study, nanoparticulate TiO2 (5 nm) was injected into the abdominal cavity of ICR mice for consecutive 14 days and the inflammatory responses of liver of mice was investigated. The results showed the obvious titanium accumulation in liver DNA, histopathological changes and hepatocytes apoptosis of mice liver, and the liver function damaged by higher doses nanoparticulate TiO2. The real-time quantitative RT-PCR and ELISA analyses showed that nanoparticulate TiO2 can significantly alter the mRNA and protein expressions of several inflammatory cytokines, including nucleic factor-κB, macrophage migration inhibitory factor, tumor necrosis factor-α, interleukin-6, interleukin-1β, cross-reaction protein, interleukin-4 and interleukin-10. Our result also implied that the inflammatory responses and liver injury may be involved in nanoparticulate TiO2-induced liver toxicity.(3) The mechanisms underlying the oxidative brain damages caused by nanoparticulate TiO2. The coefficient of the brain, the brain pathological changes and oxidative stress-mediated responses, and the accumulation of nanoparticulate TiO2 and levels of neurochemicals in the brain were examined. The results showed that high-dose nanoparticulate TiO2 could induce some neurons to turn into filamentous shapes and others into inflammatory cells. The concentration of nanoparticulate TiO2 in the brain was increased as increases in nanoparticulate TiO2 dosages used. The oxidative stress and injury of the brain occurred as nanoparticulate TiO2 appeared to trigger a cascade of reactions such as lipid peroxidation, the decreases of the total anti-oxidation capacity and activities of antioxidative enzymes, the excessive release of nitric oxide, the reduction of glutamic acid, and the downregulated level of acetylcholinesterase activities. We concluded that TiO2 nanoparticles injected at the abdominal cavity could be translocated into the brain and in turn caused the brain injury.(4) The mechanism of interactions between nanoparticulate TiO2 and SOD. The results showed that the SOD activity was greatly increased by low concentration of nanoparticulate TiO2 and inhibited by high concentration of it. The spectroscopic assays suggested that the nanoparticulate TiO2 was determined to directly bind to SOD; the binding site of nanoparticulate TiO2 to SOD was 0.256 and the binding constants were 6.54×105 L?mol-1 and 3.6×105 L?mol-1; Ti was bound with three oxygen or nitrogen atoms and a sulfur atoms of amino acid residues at the Ti–O(N) and Ti–S bond lengths of 1.86 and 2.37 ? , respectively, the binding nanoparticulate TiO2 entirely altered the secondary structure of SOD. It implied that the nanoparticulate TiO2 coordination created a new metal ion-active site form in SOD, thus leading to an enhancement in SOD activity.
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