Genotoxicity analysis of rutile titanium dioxide nanoparticles in mice after 28 days of repeated oral administration
Titanium dioxide (TiO2) or titania has demonstrated excellent potential for commercial use in various arenas, such as in the paint, in pharmaceuticals and food industry. However information on the genotoxic potential of rutile form of TiO2-NP after repeated (28 days) low dose oral exposure in major organs of the reticuloendothelial system (liver, spleen, bone marrow, lymph nodes) is not known. In this study Swiss albino male mice were gavaged TiO2-NP at sub-acute concentration (0.2, 0.4 and 0.8 mg/kg body weight) over a period of 28 days. Results revealed that TiO2-NP administered was of rutile form with mean average size of 25 nm by transmission electron microscopy. The values of PDI and Zeta potential from DLS of TiO2-NP in suspension specified that the nanomaterial was stable without much agglomeration. Chromosomal aberration assay showed that TiO2-NP was genotoxic and cytotoxic. DNA damage evaluation by comet assay confirmed that long term exposure to TiO2-NP at low concentrations can induce genotoxicity systemically in organs, such as liver, spleen, and thymus cells. Structural chromosomal aberration test from bone marrow cells revealed the clastogenicity of TiO2-NP at sub chronic low concentrations. Further in vivo studies are needed to elucidate the underlying mechanisms at the molecular level.
KeywordsClastogenicity Comet assay DNA damage Genotoxicity Rutile titania Swiss albino mice
J. Manivannan would like to acknowledge the University Grants Commission for financial assistance in the form of Research Fellowship under the Basic Scientific Research scheme (Sanction No. F.5- 21/2007dt 12.03.2014). For instrumentation facilities the authors would like to acknowledge UGC-Center for Research in Nano Science, University of Calcutta.
- 9.Donner EM, Myhre A, Brown SC, Boatman R, Warheit DB. In vivo micronucleus studies with 6 titanium dioxide materials (3 pigment-grade & 3 nanoscale) in orally-exposed rats. RegulToxicolPharmacol. 2016;74:64–74.Google Scholar
- 10.Dorier M, Béal D, Marie-Desvergne C, Dubosson M, Barreau F, Houdeau E, Herlin-Boime N, Carriere M. Continuous in vitro exposure of intestinal epithelial cells to E171 food additive causes oxidative stress, inducing oxidation of DNA bases but no endoplasmic reticulum stress. Nanotoxicology. 2017;11:751–61.PubMedGoogle Scholar
- 11.EFSA. Re-evaluation of titanium dioxide (E 171) as a food additive. 2016; http://dx.doi.org/10.2903/j.efsa.2016.4545. http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2016.4545/epdf.
- 12.El Yamani N, Collins AR, Rundén-Pran E, Fjellsbø LM, Shaposhnikov S, Zienolddiny S, Dusinska M. In vitro genotoxicity testing of four reference metal nanomaterials, titanium dioxide, zinc oxide, cerium oxide and silver: towards reliable hazard assessment. Mutagenesis. 2016;32:117–26.CrossRefPubMedGoogle Scholar
- 18.Hackenberg S, Friehs G, Froelich K, Ginzkey C, Koehler C, Scherzed A, Burghartz M, Hagen R, Kleinsasser N. Intracellular distribution, geno-and cytotoxic effects of nanosized titanium dioxide particles in the anatase crystal phase on human nasal mucosa cells. Toxicol Lett. 2010;195:9–14.CrossRefPubMedGoogle Scholar
- 23.IARC. Monographs on the Evaluation of Carcinogenic Risks to Humans. 2010; http://monographs.iarc.fr/ENG/Monographs/vol93/mono93.pdf.
- 24.Jalili P, Gueniche N, Lanceleur R, Burel A, Lavault MT, Sieg H, Böhmert L, Meyer T, Krause BC, Lampen A, Estrela-Lopis I. Investigation of the in vitro genotoxicity of two rutile TiO2 nanomaterials in human intestinal and hepatic cells and evaluation of their interference with toxicity assays. NanoImpact. 2018;11:69–81.CrossRefGoogle Scholar
- 27.Kermanizadeh A, Gaiser BK, Hutchison GR, Stone V. An in vitro liver model-assessing oxidative stress and genotoxicity following exposure of hepatocytes to a panel of engineered nanomaterials. Part FibreToxicol. 2012;9:28.Google Scholar
- 29.Kermanizadeh A, Roursgaard M, Messner S, Gunness P, Kelm JM, Møller P, Stone V, Loft S. Hepatic toxicology following single and multiple exposure of engineered nanomaterialsutilising a novel primary human 3D liver microtissue model. Part FibreToxicol. 2014;11:56.Google Scholar
- 32.McClements DJ, DeLoid G, Pyrgiotakis G, Shatkin JA, Xiao H, Demokritou P. The role of the food matrix and gastrointestinal tract in the assessment of biological properties of ingested engineered nanomaterials (iENMs): state of the science and knowledge gaps. NanoImpact. 2016;3:47–57.CrossRefPubMedGoogle Scholar
- 38.Shi H, Magaye R, Castranova V, Zhao J. Titanium dioxide nanoparticles: a review of current toxicological data. Part FibreToxicol. 2013;10:15.Google Scholar
- 40.Tavares AM, Louro H, Antunes S, Quarré S, Simar S, De Temmerman PJ, Verleysen E, Mast J, Jensen KA, Norppa H, Nesslany F. Genotoxicity evaluation of nanosized titanium dioxide, synthetic amorphous silica and multi-walled carbon nanotubes in human lymphocytes. Toxicol Vitro. 2014;28:60–9.CrossRefGoogle Scholar
- 43.Tice RR, Ivett JL. Cytogenetic analysis of bone marrow damage: toxicology of the blood and bone marrow. In: Irons RD, editor. Toxicology of the blood and bone marrow. New York: Raven Press; 1985. p. 119–40.Google Scholar
- 52.Zijno A, De Angelis I, De Berardis B, Andreoli C, Russo MT, Pietraforte D, Scorza G, Degan P, Ponti J, Rossi F, Barone F. Different mechanisms are involved in oxidative DNA damage and genotoxicity induction by ZnO and TiO2 nanoparticles in human colon carcinoma cells. Toxicol Vitro. 2015;29:1503–12.CrossRefGoogle Scholar