title: Intratracheally instilled titanium dioxide nanoparticles translocate to heart and liver and activate complement cascade in the heart of C57BL/6 mice.
abstract: An estimated 1% or less of nanoparticles (NPs) deposited in the lungs translocate to systemic circulation and enter other organs; however, this estimation may not be accurate given the low sensitivity of existing in vivo NP detection methods. Moreover, the biological effects of such low levels of translocation are unclear. We employed a nano-scale hyperspectral microscope to spatially observe and spectrally profile NPs in tissues and blood following pulmonary deposition in mice. In addition, we characterized effects occurring in blood, liver and heart at the mRNA and protein level following translocation from the lungs. Adult female C57BL/6 mice were exposed via intratracheal instillation to 18 or 162 µg of industrially relevant titanium dioxide nanoparticles (nano-TiO2) alongside vehicle controls. Using the nano-scale hyperspectral microscope, translocation to heart and liver was confirmed at both doses, and to blood at the highest dose, in mice analyzed 24 h post-exposure. Global gene expression profiling and ELISA analysis revealed activation of complement cascade and inflammatory processes in heart and specific activation of complement factor 3 in blood, suggesting activation of an early innate immune response essential for particle opsonisation and clearance. The liver showed a subtle response with changes in the expression of genes associated with acute phase response. This study characterizes the subtle systemic effects that occur in liver and heart tissues following pulmonary exposure and low levels of translocation of nano-TiO2 from lungs.
authors.affiliation: a Environmental Health Science and Research Bureau, Health Canada , Ottawa , Ontario , Canada .
authors.forename: Mainul
authors.initials: M
authors.lastname: Husain
authors.affiliation: a Environmental Health Science and Research Bureau, Health Canada , Ottawa , Ontario , Canada .
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.affiliation: b The Danish NanoSafety Centre, National Research Centre for the Working Environment , Copenhagen , Denmark .
authors.forename: Anne T
authors.initials: AT
authors.lastname: Saber
authors.affiliation: a Environmental Health Science and Research Bureau, Health Canada , Ottawa , Ontario , Canada .
authors.forename: Nathalie
authors.initials: N
authors.lastname: Decan
authors.affiliation: b The Danish NanoSafety Centre, National Research Centre for the Working Environment , Copenhagen , Denmark .
authors.forename: Nicklas R
authors.initials: NR
authors.lastname: Jacobsen
authors.affiliation: b The Danish NanoSafety Centre, National Research Centre for the Working Environment , Copenhagen , Denmark .
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: a Environmental Health Science and Research Bureau, Health Canada , Ottawa , Ontario , Canada .
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
authors.affiliation: b The Danish NanoSafety Centre, National Research Centre for the Working Environment , Copenhagen , Denmark .|c Institute of Public Health, University of Copenhagen , Copenhagen , Denmark , and.
authors.forename: Hakan
authors.initials: H
authors.lastname: Wallin
authors.affiliation: b The Danish NanoSafety Centre, National Research Centre for the Working Environment , Copenhagen , Denmark .|d Department of Micro- and Nanotechnology , Technical University of Denmark , Kgs, Lyngby , Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.affiliation: a Environmental Health Science and Research Bureau, Health Canada , Ottawa , Ontario , Canada .
authors.forename: Sabina
authors.initials: S
authors.lastname: Halappanavar
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D003167:Complement Activation / Q000187:drug effects*; D003165:Complement System Proteins / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects*; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008168:Lung / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D014018:Tissue Distribution; D014025:Titanium / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D018836:Inflammation Mediators; C009495:titanium dioxide; D003165:Complement System Proteins; D014025:Titanium
keywords: Complement cascade; gene expression; hyperspectral microscopy; inflammation; nanoparticles; translocation