title: Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation.
abstract: We investigated gene expression, protein synthesis, and particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO2). Female C57BL/6 mice were exposed to rutile nano-TiO2 via single intratracheal instillations of 18, 54, and 162μg/mouse. Mice were sampled 1, 3, and 28days post-exposure. The deposition of nano-TiO2 in the lungs was assessed using nanoscale hyperspectral microscopy. Biological responses in the pulmonary system were analyzed using DNA microarrays, pathway-specific real-time RT-PCR (qPCR), gene-specific qPCR arrays, and tissue protein ELISA. Hyperspectral mapping showed dose-dependent retention of nano-TiO2 in the lungs up to 28days post-instillation. DNA microarray analysis revealed approximately 3000 genes that were altered across all treatment groups (±1.3 fold; p<0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein level. Although no influx of neutrophils was detected at the low dose, changes in the expression of several genes and proteins associated with inflammation were observed. Resolving inflammation at the medium dose, and lack of neutrophil influx in the lung fluid at the low dose, were associated with down-regulation of genes involved in ion homeostasis and muscle regulation. Our gene expression results imply that retention of nano-TiO2 in the absence of inflammation over time may potentially perturb calcium and ion homeostasis, and affect smooth muscle activities.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9, Canada. mainul.husain@hc-sc.gc.ca
authors.forename: Mainul
authors.initials: M
authors.lastname: Husain
authors.forename: Anne T
authors.initials: AT
authors.lastname: Saber
authors.forename: Charles
authors.initials: C
authors.lastname: Guo
authors.forename: Nicklas R
authors.initials: NR
authors.lastname: Jacobsen
authors.forename: Keld A
authors.initials: KA
authors.lastname: Jensen
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.forename: Hakan
authors.initials: H
authors.lastname: Wallin
authors.forename: Sabina
authors.initials: S
authors.lastname: Halappanavar
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D007249:Inflammation / Q000378:metabolism; D008168:Lung / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D053768:Metal Nanoparticles / Q000032:analysis / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D014025:Titanium / Q000032:analysis / Q000633:toxicity*
chemical_list: C009495:titanium dioxide; D014025:Titanium