title: Long-term inhalation exposure to nickel nanoparticles exacerbated atherosclerosis in a susceptible mouse model.
abstract: BACKGROUND
  Because associations have been reported between inhaled ambient ultrafine particles and increased risk of cardiopulmonary disease, it has been suggested that inhaled engineered nanoparticles (NPs) may also induce adverse effects on the cardiovascular system.
  
  
  OBJECTIVE
  We examined the long-term cardiovascular effects of inhaled nickel hydroxide NPs (nano-NH) using a sensitive mouse model.
  
  
  METHODS
  Hyperlipidemic, apoprotein E-deficient (ApoE-/-) mice were exposed to nano-NH at either 0 or 79 μg Ni/m3, via a whole-body inhalation system, for 5 hr/day, 5 days/week, for either 1 week or 5 months. We measured various indicators of oxidative stress and inflammation in the lung and cardiovascular tissue, and we determined plaque formation on the ascending aorta.
  
  
  RESULTS
  Inhaled nano-NH induced significant oxidative stress and inflammation in the pulmonary and extrapulmonary organs, indicated by up-regulated mRNA levels of certain antioxidant enzyme and inflammatory cytokine genes; increased mitochondrial DNA damage in the aorta; significant signs of inflammation in bronchoalveolar lavage fluid; changes in lung histopathology; and induction of acute-phase response. In addition, after 5-month exposures, nano-NH exacerbated the progression of atherosclerosis in ApoE-/- mice.
  
  
  CONCLUSIONS
  This is the first study to report long-term cardiovascular toxicity of an inhaled nanomaterial. Our results clearly demonstrate that long-term exposure to inhaled nano-NH can induce oxidative stress and inflammation, not only in the lung but also in the cardiovascular system, and that this stress and inflammation can ultimately contribute to progression of atherosclerosis in ApoE-/- mice.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA.
authors.forename: Gi Soo
authors.initials: GS
authors.lastname: Kang
authors.forename: Patricia Anne
authors.initials: PA
authors.lastname: Gillespie
authors.forename: Albert
authors.initials: A
authors.lastname: Gunnison
authors.forename: Andre Luis
authors.initials: AL
authors.lastname: Moreira
authors.forename: Kam-Meng
authors.initials: KM
authors.lastname: Tchou-Wong
authors.forename: Lung-Chi
authors.initials: LC
authors.lastname: Chen
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced*; D004272:DNA, Mitochondrial / Q000187:drug effects; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects; D008297:Male; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D009532:Nickel / Q000008:administration & dosage / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004272:DNA, Mitochondrial; D009532:Nickel