title: Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response.
abstract: We applied transcriptional profiling to elucidate the mechanisms associated with pulmonary responses to titanium dioxide (TiO2 ) nanoparticles (NPs) of different sizes and surface coatings, and to determine if these responses are modified by NP size, surface area, surface modification, and embedding in paint matrices. Adult C57BL/6 mice were exposed via single intratracheal instillations to free forms of TiO2 NPs (10, 20.6, or 38 nm in diameter) with different surface coatings, or TiO2 NPs embedded in paint matrices. Controls were exposed to dispersion medium devoid of NPs. TiO2 NPs were characterized for size, surface area, chemical impurities, and agglomeration state in the exposure medium. Pulmonary transcriptional profiles were generated using microarrays from tissues collected one and 28 d postexposure. Property-specific pathway effects were identified. Pulmonary protein levels of specific inflammatory cytokines and chemokines were confirmed by ELISA. The data were collapsed to 659 differentially expressed genes (P ≤ 0.05; fold change ≥ 1.5). Unsupervised hierarchical clustering of these genes revealed that TiO2 NPs clustered mainly by postexposure timepoint followed by particle type. A pathway-based meta-analysis showed that the combination of smaller size, large deposited surface area, and surface amidation contributes to TiO2 NP gene expression response. Embedding of TiO2 NP in paint dampens the overall transcriptional effects. The magnitude of the expression changes associated with pulmonary inflammation differed across all particles; however, the underlying pathway perturbations leading to inflammation were similar, suggesting a generalized mechanism-of-action for all TiO2 NPs. Thus, transcriptional profiling is an effective tool to determine the property-specific biological/toxicity responses induced by nanomaterials.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada.
authors.forename: Sabina
authors.initials: S
authors.lastname: Halappanavar
authors.forename: Anne Thoustrup
authors.initials: AT
authors.lastname: Saber
authors.forename: Nathalie
authors.initials: N
authors.lastname: Decan
authors.forename: Keld Alstrup
authors.initials: KA
authors.lastname: Jensen
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.forename: Nicklas Raun
authors.initials: NR
authors.lastname: Jacobsen
authors.forename: Charles
authors.initials: C
authors.lastname: Guo
authors.forename: Jacob
authors.initials: J
authors.lastname: Rogowski
authors.forename: Ismo K
authors.initials: IK
authors.lastname: Koponen
authors.forename: Marcus
authors.initials: M
authors.lastname: Levin
authors.forename: Anne Mette
authors.initials: AM
authors.lastname: Madsen
authors.forename: Rambabu
authors.initials: R
authors.lastname: Atluri
authors.forename: Valentinas
authors.initials: V
authors.lastname: Snitka
authors.forename: Renie K
authors.initials: RK
authors.lastname: Birkedal
authors.forename: David
authors.initials: D
authors.lastname: Rickerby
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.forename: Håkan
authors.initials: H
authors.lastname: Wallin
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053768:Metal Nanoparticles / Q000009:adverse effects*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D040901:Proteomics; D046888:Tissue Array Analysis; D014025:Titanium / Q000009:adverse effects*
chemical_list: C009495:titanium dioxide; D014025:Titanium
keywords: hyperspectral microscopy; lung inflammation; matrix-embedded nanomaterials; paint dusts; titanium dioxide nanoparticles; toxicogenomics