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There are many studies concerning titanium dioxide (TiO₂) nanoparticles (NP) toxicity. Nevertheless, there are few publications comparing <i>in vitro</i> and <i>in vivo</i> exposure, and even less comparing air–liquid interface exposure (ALI) with other <i>in vitro</i> and <i>in vivo</i> exposures. 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 assessed <i>in vitro</i> by WST-1 and LDH assays after the exposure of NR8383 cells to TiO₂ NP sample. To evaluate <i>in vitro</i> gene expression profile, NR8383 cells were exposed to TiO₂ NP during 4 h at 3 cm² of TiO₂ NP/cm² of cells or 19 μg/mL, in two settings—submerged cultures and ALI. For the <i>in vivo</i> study, Fischer 344 rats were exposed by inhalation to a nanostructured aerosol at a concentration of 10 mg/m³, 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 TiO₂ NP on NR8383 cells. Despite the absence of toxicity at the doses studied, the different exposures to TiO₂ NP 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 of <i>Ccl4</i>, <i>Osm</i>, <i>Ccl7</i> and <i>Bcl3</i> genes which could be suggested as early response biomarkers after exposure to TiO₂ NP. On the other hand, the comparison of the three models helped us to validate the alternative ones, namely submerged and ALI approaches.