title: Toxicogenomics analysis of mouse lung responses following exposure to titanium dioxide nanomaterials reveal their disease potential at high doses.
abstract: Titanium dioxide nanoparticles (TiO2NPs) induce lung inflammation in experimental animals. In this study, we conducted a comprehensive toxicogenomic analysis of lung responses in mice exposed to six individual TiO2NPs exhibiting different sizes (8, 20 and 300nm), crystalline structure (anatase, rutile or anatase/rutile) and surface modifications (hydrophobic or hydrophilic) to investigate whether the mechanisms leading to TiO2NP-induced lung inflammation are property specific. A detailed histopathological analysis was conducted to investigate the long-term disease implications of acute exposure to TiO2NPs. C57BL/6 mice were exposed to 18, 54, 162 or 486 µg of TiO2NPs/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 TiO2NPs induced lung inflammation as measured by the neutrophil influx in BALF, rutile-type TiO2NPs induced higher inflammation with the hydrophilic rutile TiO2NP showing the maximum increase. Accordingly, the rutile TiO2NPs 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 TiO2NPs at the highest dose tested. Among the anatase, the smallest TiO2NP of 8nm showed the maximum response. The anatase TiO2NP of 300nm 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 µg/mouse). Although the dose at which the pathological changes were observed is considered physiologically high, the study highlights the disease potential of certain TiO2NPs of specific properties.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Tunney's Pasture Bldg. 8, Ottawa, Ontario K1A 0K9, Canada and.
authors.forename: Luna
authors.initials: L
authors.lastname: Rahman
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Tunney's Pasture Bldg. 8, Ottawa, Ontario K1A 0K9, Canada and.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.affiliation: Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Johnston
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Tunney's Pasture Bldg. 8, Ottawa, Ontario K1A 0K9, Canada and.
authors.forename: Andrew
authors.initials: A
authors.lastname: William
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Tunney's Pasture Bldg. 8, Ottawa, Ontario K1A 0K9, Canada and sabina.halappanavar@hc-sc.gc.ca.
authors.forename: Sabina
authors.initials: S
authors.lastname: Halappanavar
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D007249:Inflammation; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D010316:Particle Size; D011658:Pulmonary Fibrosis / Q000139:chemically induced; D014025:Titanium / Q000494:pharmacology / Q000633:toxicity*; D043922:Toxicogenetics; D059467:Transcriptome / Q000187:drug effects*
chemical_list: C009495:titanium dioxide; D014025:Titanium