Toxicological characteristics of nanoparticulate anatase titanium dioxide in mice
Introduction
Titanium dioxide (TiO2) occurs primarily in the form of the minerals rutile, anatase, brookite, and as the iron-containing mineral ilmenite (FeTiO3). The major source of TiO2 is ilmenite, while rutile and anatase pigments are mainly manufactured commercially. TiO2 is a versatile compound that has already been used in nanoparticulate form in a variety of consumer products such as sunscreens that are surface coated with e.g. silica and other cosmetics [1], specialist coatings and paints [2], [3], and in industrial photocatalytic processes [4], [5]. Therefore, nanoparticulate TiO2 has probably entered in the environment, even though its current levels are unknown. Generally TiO2 has been considered biologically inactive in experimental animals [6], [7], [8], [9] and humans [10], [11], [12], [13]. However, the injury of liver function was recently observed in mice exposed to nanoparticulate TiO2 [14], [15], [16], [17]. Wang et al. reported that high-dose nanoparticulate TiO2 (25 and 80 nm) with oral gavage increased the ratio of alanine aminotransferase to aspartate aminotransferase, the activity of lactate dehydrogenase and the coefficient of the liver, and caused the hepatocyte necrosis [14]. Liu et al. found that high-dose nanoparticulate anatase TiO2 (5 nm) with intraperitoneal injection could damage liver function [15] and induced an oxidative attack in the mouse liver [16]. The histopathological changes and hepatocytes apoptosis of the mouse liver were observed; and the liver function damaged and inflammatory cascade by high-doses nanoparticulate anatase TiO2 (5 nm) with intraperitoneal injection were showed to be closely related to significant alteration of the mRNA and protein expressions of several inflammatory cytokines [17]. However, it remained unclear whether these liver function damages in mice treated with nanoparticulate TiO2 also have the changes of hematological indices and the reduction of immune response.
Lymphocyte proliferation is the important phase in immune response of the animal body [18], [19]. T lymphocyte and B lymphocyte have receptors to identify antigen and mitogen. Could nanoparticulate TiO2 affect T lymphocytes (such as CD3+, CD4+, and CD8+ cells) and B lymphocyte proliferation in mice when the liver function was damaged? In addition, hematological indices are important parameters for the evaluation of the animal and human physiological status. Hematological parameters are closely related to the animal's response to the environment, i.e., any change of hematological indices is indicative of possible effects on the hematological characteristics exerted by the environment where animal live [20]. They can provide substantial diagnostic information once reference values are established under exposure to nanoparticulate TiO2 conditions. Evaluation of the hemogram involves the determination of the total erythrocyte count (RBC), total white blood cell count (WBC), hematocrit (PCV), haemoglobin concentration (HGB), erythrocyte indices, white blood cell (WBC) differential count and the evaluation of stained peripheral blood films [21]. Thrombocytes (PCT), next to erythrocytes, are known to be one of the most abundant blood cells.
In order to investigate the intrinsic hazard potential of nanoparticulate TiO2 particles that may have entered into animals and humans from the environment, we studied the toxic effects of nanoparticulate anatase TiO2 (5 nm) on mice after 30 days of intragastric administration. The immune response in these mice treated with nanoparticulate anatase TiO2 was measured by T lymphocyte (such as CD3, CD4, and CD8), B lymphocyte and natural killer lymphocyte proliferation, hematological characteristics. We also examined biochemical parameters of liver functions and histopathological changes of these nanoparticulate anatase TiO2-treated mice.
Section snippets
Chemicals and preparation
Nanoparticulate anatase TiO2 was prepared via controlled hydrolysis of titanium tetrabutoxide. The details of the synthesis are as follows [22]: Colloidal titanium dioxide was prepared via controlled hydrolysis of titanium tetrabutoxide. In a typical experiment, 1 ml of Ti (OC4H9) 4 dissolved in 20 ml of anhydrous isopropanol was added dropwise to 50 ml of double-distilled water adjusted to pH 1.5 with nitric acid under vigorous stirring at room temperature. Then, the temperature was raised to 60
Growth and the coefficients of organs
During administration, animals were all at growth state. The daily behaviors such as eating, drinking and activity in nanoparticulate TiO2-treated groups were as normal as the control group. After 30 days, the mice were weighted, various organs were collected and also weighted. Table 1 shows the net weight increase and the coefficients of the organs to the body weight (milligrams, wet weight of tissues/grams, body weight). No significant differences in the body weight and coefficients of the
Discussion
Our results showed that the intragastric administration of nanoparticulate anatase TiO2 of 125 or 250 mg/kg (BW) everyday (“every other day” was described in M&M) for 30 days can significantly decrease the body weight and increase the coefficients of the liver, kidney, spleen and thymus of mice. We observed blur in the large area and congestion in the liver tissue. The damages of liver function was also caused by 250 mg/kg BW nanoparticulate anatase TiO2, as evidenced by the increased activities
Conclusion
Our study showed that mice treated with 125 and 250 mg/kg BW nanoparticulate anatase TiO2 for consecutive 30 days display decreased body weight, increased coefficients of the liver, kidney, spleen and thymus and seriously damaged liver function. We also observed that these nanoparticulate anatase TiO2-treated mice decrease WBC, RBC, HGB, MCHC, PCT, Ret, and T lymphocytes, the ratio of CD4 to CD8, B lymphocytes, NK lymphocytes, and IL-2 activity, but increase MCV, MHC, RDW, PLT, HCT, MPV, NO. But
Acknowledgements
This work was supported by the National Natural Science Foundation of China (grant No. 30901218) and by the Medical Development Foundation of Suzhou University (grant no.EE120701) and by the National Bringing New Ideas Foundation of Student of China (grant no.57315427, 57315927).
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2022, Journal of Trace Elements in Medicine and BiologyCitation Excerpt :The elevation of liver enzymes suggests the hepatocytes' injury or damage and the release of these enzymes to the extracellular fluids [64]; however, the elevation of kidney indices revealed the damage or dysfunction of the kidney [65]. Moreover, the disturbances in lipid profile indicate that these nanoparticles affect the function of lipoprotein lipase enzyme or the transferring and the removing of the lipid fractions [66,67]. The decrease in HDL-Cho and the increase in Cho, TriG, and LDL-Cho also pointed out that exposure to TiO2-NPs may be a causative risk for cardiovascular diseases [2,68].
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These authors contributed equally to this work.