Genotoxic responses to titanium dioxide nanoparticles and fullerene in gpt delta transgenic MEF cells

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Titanium dioxide (TiO<jats:sub>2</jats:sub>) nanoparticles and fullerene (C<jats:sub>60</jats:sub>) are two attractive manufactured nanoparticles with great promise in industrial and medical applications. However, little is known about the genotoxic response of TiO<jats:sub>2</jats:sub> nanoparticles and C<jats:sub>60</jats:sub> in mammalian cells. In the present study, we determined the mutation fractions induced by either TiO<jats:sub>2</jats:sub> nanoparticles or C<jats:sub>60</jats:sub> in <jats:italic>gpt</jats:italic> delta transgenic mouse primary embryo fibroblasts (MEF) and identified peroxynitrite anions (ONOO<jats:sup>-</jats:sup>) as an essential mediator involved in such process.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Both TiO<jats:sub>2</jats:sub> nanoparticles and C<jats:sub>60</jats:sub> dramatically increased the mutation yield, which could be abrogated by concurrent treatment with the endocytosis inhibitor, Nystatin. Under confocal scanning microscopy together with the radical probe dihydrorhodamine 123 (DHR 123), we found that there was a dose-dependent formation of ONOO<jats:sup>-</jats:sup> in live MEF cells exposed to either TiO<jats:sub>2</jats:sub> nanoparticles or C<jats:sub>60</jats:sub>, and the protective effects of antioxidants were demonstrated by the nitric oxide synthase (NOS) inhibitor, N<jats:sup>G</jats:sup>-methyl-L-arginine (L-NMMA). Furthermore, suppression of cyclooxygenase-2 (COX-2) activity by using the chemical inhibitor NS-398 significantly reduced mutation frequency of both TiO<jats:sub>2</jats:sub> nanoparticles and C<jats:sub>60</jats:sub>.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Our results provided novel information that both TiO<jats:sub>2</jats:sub> nanoparticles and C<jats:sub>60</jats:sub> were taken up by cells and induced kilo-base pair deletion mutations in a transgenic mouse mutation system. The induction of ONOO<jats:sup>-</jats:sup> may be a critical signaling event for nanoparticle genotoxicity.</jats:p> </jats:sec>