Toxicity of TiO 2 Nanoparticles: Validation of Alternative Models.

There are many studies concerning titanium dioxide (TiO2) nanoparticles (NP) toxicity. Nevertheless, there are few publications comparingin vitroandin vivoexposure, and even less comparing air-liquid interface exposure (ALI) with otherin vitroandin vivoexposures. The identification and validation of common markers under different exposure conditions are relevant for the development of smart and quick nanotoxicity tests. In this work, cell viability was assessedin vitroby WST-1 and LDH assays after the exposure of NR8383 cells to TiO2NP sample. To evaluatein vitrogene expression profile, NR8383 cells were exposed to TiO2NP during 4 h at 3 cm(2)of TiO2NP/cm(2)of cells or 19 mu g/mL, in two settings-submerged cultures and ALI. For thein vivostudy, Fischer 344 rats were exposed by inhalation to a nanostructured aerosol at a concentration of 10 mg/m(3), 6 h/day, 5 days/week for 4 weeks. This was followed immediately by gene expression analysis. The results showed a low cytotoxic potential of TiO2NP on NR8383 cells. Despite the absence of toxicity at the doses studied, the different exposures to TiO2NP induce 18 common differentially expressed genes (DEG) which are involved in mitosis regulation, cell proliferation and apoptosis and inflammation transport of membrane proteins. Among these genes, we noticed the upregulation ofCcl4,Osm,Ccl7andBcl3genes which could be suggested as early response biomarkers after exposure to TiO2NP. On the other hand, the comparison of the three models helped us to validate the alternative ones, namely submerged and ALI approaches.