Toxicogenomics analysis of mouse lung responses following exposure to titanium dioxide nanomaterials reveal their disease potential at high doses

Titanium dioxide nanoparticles (TiO2 NPs) induce lung inflammation in experimental animals. In this study, we conducted a comprehensive toxicogenomic analysis of lung responses in mice exposed to six individual TiO2 NPs exhibiting different sizes (8, 20 and 300 nm), crystalline structure (anatase, rutile or anatase/rutile) and surface modifications (hydrophobic or hydrophilic) to investigate whether the mechanisms leading to TiO2 NP-induced lung inflammation are property specific. A detailed histopathological analysis was conducted to investigate the long-term disease implications of acute exposure to TiO2 NPs. C57BL/6 mice were exposed to 18, 54, 162 or 486 mu g of TiO2 NPs/mouse via single intratracheal instillation. Controls were exposed to dispersion medium only. Bronchoalveolar lavage fluid (BALF) and lung tissue were sampled on 1, 28 and 90 days post-exposure. Although all TiO2 NPs induced lung inflammation as measured by the neutrophil influx in BALF, rutile-type TiO2 NPs induced higher inflammation with the hydrophilic rutile TiO2 NP showing the maximum increase. Accordingly, the rutile TiO2 NPs induced higher number of differentially expressed genes. Histopathological analysis of lung sections on Day 90 post-exposure showed increased collagen staining and fibrosis-like changes following exposure to the rutile TiO2 NPs at the highest dose tested. Among the anatase, the smallest TiO2 NP of 8 nm showed the maximum response. The anatase TiO2 NP of 300 nm was the least responsive of all. The results suggest that the severity of lung inflammation is property specific; however, the underlying mechanisms (genes and pathways perturbed) leading to inflammation were the same for all particle types. While the particle size clearly influenced the overall acute lung responses, a combination of small size, crystalline structure and hydrophilic surface contributed to the long-term pathological effects observed at the highest dose (486 mu g/mouse). Although the dose at which the pathological changes were observed is considered physiologically high, the study highlights the disease potential of certain TiO2 NPs of specific properties.