Investigation of genotoxic and cytotoxic effects of micro- and nanosized titanium dioxide in six organs of mice in vivo

Titanium dioxide is manufactured worldwide in large quantities for use in a wide range of applications including as food additives, in cosmetics and pigments for coloring ingested and externally applied drugs. Although TiO2 is chemically inert it can cause negative health effects, such as lung cancer in rats. However, the mechanisms involved in TiO2-induced genotoxicity and carcinogenicity have not been clearly defined and are poorly studied in vivo. In the present research genotoxicity and carcinogenicity of titanium dioxide were studied in a mouse model. We treated CBAB6F1 mice by oral gavage with titanium dioxide particles (microsized, TDM, 160 nm; nanosized, TDN, 33 nm) in doses of 40, 200 and 1000 mg/kg bw, daily for seven days. Genotoxic effects were analyzed in the cells of brain, liver and bone marrow by means of the Comet assay and in the cells of bone marrow, forestomach, colon and testis with a poly-organ karyological assay (analysis of micronuclei, nuclear protrusions, atypical nuclei, multinucleated cells, mitotic and/or apoptotic index). TDM induced DNA-damage and micronuclei in bone-marrow cells and TDN induced DNA-damage in the cells of bone marrow and liver. TDM and TDN increased the mitotic index in forestomach and colon epithelia, the frequency of spermatids with two and more nuclei, and apoptosis in forestomach (only TDN) and testis. This is one of the first poly-organ studies of TDM- and TDN-induced genotoxicity in vivo in mice. These effects are caused by a secondary genotoxic mechanism associated with inflammation and/or oxidative stress. Given the increasing use of TiO2 nanoparticles, these findings indicate a potential health hazard associated with exposure to TiO2 particles.

► Titanium dioxide microparticles (TDM, 160 nm) induced DNA-damage and micronuclei in the bone marrow cells.
► Titanium dioxide nanoparticles (TDN, 33 nm) induced DNA-damage in the cells of bone marrow and liver.
► TDM and TDN increased the mitotic index in the forestomach and colon epithelia, frequency of spermatides with two and more nuclei and apoptosis in forestomach (only TDN) and testis.
► Both kinds of particles were injected to mice per os in doses 40, 200 and 1000 mg/kg daily for 7 days.