Toxic effect of titanium dioxide nanoparticles on morphological characteristics of thymus

Cover Page


Aim. Study of effects of titanium dioxide nanoparticles administered orally on the rodent thymus morphological and functional state.

Methods. The study used classical morphological approaches and specific markers of proliferation - Ki-67, apoptosis - p53 protein and macrophages - CD68, which allow adequately identifying not only the cells themselves, but also their functional state. The rodent thymus was analyzed after oral administration (10 mg/kg of body weight of the animal, 28 days) of the TiO2 nanoparticles (rutile form, 40-60 nm) obtained by diluting the TiO2 powder in distilled water. Aggregation of the nanoparticles was prevented by processing a suspension of nanodispersed TiO2 in an ultrasonic bath. The rats of the control group were orally injected with distilled water in the same volume. Serial paraffin sections of the thymus were stained with hematoxylin-eosin, picrofuxin according to Van Gieson, immunohistochemical staining was performed with antibodies to Ki-67, CD68, p53.

Results. Significant changes of the tissue of thymus gland under the influence of TiO2 nanoparticles were revealed. In the thymus of experimental animals, a decrease in the proportion of cortex was found to be 17.6 %, a significant decrease in the density of the cell population due to decrease in the number of thymocytes was demonstrated. Immunohistochemical typing revealed that under the influence of TiO2 nanoparticles, a decrease in the number of Ki-67-positive cells in the cortex of the lobule of the thymus gland was observed, which indicates the inhibition of proliferation in these conditions. Under the influence of TiO2 nanoparticles, an increase of the amount of cells entering apoptosis in the cortex of the thymus segment of the experimental group by 5.18 times was observed, as evidenced by the results of immunohistochemical study of the expression of apoptosis marker p53 protein. Perhaps, as a compensatory mechanism there is a pronounced increase in the number of macrophages, as indicated by an increase in the average number of CD68 immunopositive cells in the cortex of the thymus of the test group by 2.61, and in the brain substance by 1.35.

Conclusion. The revealed morphological and functional changes of the thymus with oral administration of TiO2 nanoparticles indicate their immunosuppressive effect.

L A Sharafutdinova

Bashkir State University

Author for correspondence.
Ufa, Russia

K N Sinel’nikov

Bashkir State University

Ufa, Russia

V V Valiullin

Kazan State Medical University

Kazan, Russia

  • Karimipour M., Zirak Javanmard M., Ahmadi A., Jafari A. Oral administration of titanium dioxide nanoparticle through ovarian tissue alterations impairs mice embryonic development. J. Reprod. Biomed (Yazd). 2018; 16 (6): ­397–404. doi: 10.29252/ijrm.16.6.397.
  • Winkler H.C., Notter T.,Meyer U.,Naegeli H. Critical review of the safety assessment of titanium dioxide additives in food. J. Nanobiotechnology. 2018; 16: 51. doi: 10.1186/s12951-018-0376-8.
  • Weir A., Westerhoff P., Fabricius L., Hristovski K., von Goetz N. Titanium dioxide nanoparticles in food and personal care products. Environ. Sci. Technol. 2012; 46: 2242–2250. doi: 10.1021/es204168d.
  • Kovaleva N.Yu., Raevskaya E.G., Roshchin A.V. Aspects of nanomaterial safety: nanosafety, nanotoxicology, nanoinformatics. Khimicheskaya bezopasnost'. 2017; 1 (2): 44–87. (In Russ.)
  • Wang X., Reece S.P., Brown J.M. Immunotoxi­cological impact of engineered nanomaterial exposure: mechanisms of immune cell modulation. Toxicol. Mech. Methods. 2013; 23 (3): 168–177. doi: 10.3109/­15376516.2012.757686.
  • Van Loveren H., Vos J.G., De Waal E.J. Testing im­munotoxicity of chemicals as a guide for testing approaches for pharmaceuticals. Drug Info. J. 1996; 30: 275–279. doi: 10.1177/009286159603000132.
  • Hong F., Zhou Y., Zhou Y., Wang L. Immunotoxic effects of thymus in mice following exposure to nano­particulate TiO2. Environ. Toxicol. 2017; 32 (10): ­2234–2243. doi: 10.1002/tox.22439.
  • Ngobili T.A., Daniele M.A. Nanoparticles and direct immunosuppression. Exp. Biol. Med. (Maywood). 2016; 241 (10): 1064–1073. doi: 10.1177/1535370216650053.
  • Kvaratskheliya A.G., Klochkova S.V., Nikityuk D.B., Alekseeva N.T. Morphological characteristics of the thymus and spleen under different factors of ori­gin. Zhurnal anatomii i gistopatologii. 2016; 5 (3): 77–83. (In Russ.)
  • Susan A. Elmore. Enhanced Histopathology of the Immune System: A Review and Update. Toxicol. Pathol. 2012; 40 (2): 148–156. doi: 10.1177/0192623311427571.
  • Moon E.Y., Yi G.H., Kang J.S., Lim J.S., Kim H.M., Pyo S. An increase in mousetumorgrowth by an in vivo immunomodulating effect of titanium dioxide nano­particles. J. Immunotoxicol. 2011; 8 (1): 56–67. DOI: 10.3109/
  • X.2010.543995.
  • Dua Y., Liu J., Ma L., Li N., Liu H., Wang J., Zheng L., Liu C., Wang X., Zhao X., Yan J., Wang S., Wang H., Zhang X., Hang G.F. Toxicological charac­teristics of nanoparticulate anatasetitanium dioxide in mice. Biomaterials. 2010; 31: 894–899. DOI: 10.1016/
  • j.biomaterials.­2009.10.003.
  • Eom H.J., Choi J. P38 MAPK Activation, DNA Da­mage, Cell Cycle Arrest and Apoptosis As Mechanisms of Toxicity of Silver Nanoparticles in Jurkat T Cells.Environ. Sci. Technol. 2010; 44: 8337–8342. doi: 10.1021/es1020668.
  • Fröhlich E. Cellular Targets and Mechanisms in the Cytotoxic Action of Non-biodegradable Engineered Nanoparticles. Curr. Drug. Metab. 2013. 14 (9): 976–988. doi: 10.2174/1389200211314090004.
  • Liu Y., Gao Y., Liu Y., Li B., Chen C., Wu G. Oxidative stress and acute changes in murine brain tissues after nasal instillation of copper particles with different sizes. J. Nanosci. Nanotechnol. 2014; 14 (6): 4534–4540. doi: 10.1166/jnn.2014.8290.
  • Park E., Yi J., Chung K. Oxidative stress and apoptosis induced by titanium dioxide nanoparticles in cultured BEAS-2B cells. Toxicol. Lett. 2008. 180: 222–229. doi: 10.1016/j.toxlet.2008.06.869.


Abstract - 21

PDF (Russian) - 35


© 2018 Sharafutdinova L.A., Sinel’nikov K.N., Valiullin V.V.

Creative Commons License

This work is licensed
under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Свидетельство о регистрации СМИ ЭЛ № ФС 77-70434 от 20 июля 2017 года выдано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор)