title: Effect of co-exposure to nickel and particulate matter on insulin resistance and mitochondrial dysfunction in a mouse model.
abstract: BACKGROUND
  It has been well recognized that toxicity of fine ambient air particulate matter (PM(2.5)) may depend on its chemical constituents, including components such as soluble metals that may theoretically exert distinctive effects. We have recently demonstrated an important effect of PM(2.5) on metabolic function. Since transition metals, such as nickel (Ni), represent an important component of exposure in certain environments, and may significantly influence the toxicity of inhalational exposure, we investigated the effects of Ni as a variable component of ambient PM(2.5) exposure.
  
  
  METHODS
  Male ApoE knockout mice were exposed to filtered air (FA), fine-sized nickel sulfate particles alone (Ni) at 0.44 μg/m(3), concentrated ambient air PM(2.5) (CAPs) at a mean of 70 μg/m(3), or CAPs+Ni in Tuxedo, NY, 6 hours/day, 5 days/week, for 3 months.
  
  
  RESULTS
  Exposure to Ni, irrespective of co-exposure to CAPs, resulted in body weight gain, while exposure to CAPs+Ni significantly enhanced fasting glucose and worsened insulin resistance measures (HOMA-IR), when compared with exposure to CAPs alone. CAPs+Ni exposure induced a significant decrease in phosphorylation of AMP-activated protein kinase (AMPK) α. Exposure to Ni or CAPs+Ni significantly induced microcirculatory dysfunction and increased monocytic cell infiltration into lung and adipose, and decreased uncoupling protein 1 expression at gene and protein levels and several brown adipocyte-specific genes in adipose tissue.
  
  
  CONCLUSIONS
  Ni exposure has effects on metabolic and inflammatory parameters that are comparable to that of CAPs. Additionally, Ni synergistically exacerbates CAPs-induced adverse effects on some of, but not all of, these parameters, that may be mediated via the AMPK signaling pathway. These findings have important implications for inhaled transition metal toxicity that may exert synergistic effects with other PM(2.5) components.
authors.affiliation: Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Rao
authors.forename: Tse-Yao
authors.initials: TY
authors.lastname: Wang
authors.forename: Silis Y
authors.initials: SY
authors.lastname: Jiang
authors.forename: Zhekang
authors.initials: Z
authors.lastname: Ying
authors.forename: Cuiqing
authors.initials: C
authors.lastname: Liu
authors.forename: Aixia
authors.initials: A
authors.lastname: Wang
authors.forename: Mianhua
authors.initials: M
authors.lastname: Zhong
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Deiuliis
authors.forename: Andrei
authors.initials: A
authors.lastname: Maiseyeu
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
authors.forename: Morton
authors.initials: M
authors.lastname: Lippmann
authors.forename: Lung-Chi
authors.initials: LC
authors.lastname: Chen
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001786:Blood Glucose / Q000032:analysis; D016207:Cytokines / Q000097:blood; D004357:Drug Synergism; D005951:Glucose Tolerance Test; D019570:Inhalation Exposure / Q000009:adverse effects*; D007333:Insulin Resistance / Q000276:immunology; D007473:Ion Channels / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics; D053142:Mitochondrial Size / Q000187:drug effects; D009532:Nickel / Q000633:toxicity*; D010316:Particle Size; D052638:Particulate Matter / Q000633:toxicity*; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D000071256:Uncoupling Protein 1
chemical_list: D000393:Air Pollutants; D001057:Apolipoproteins E; D001786:Blood Glucose; D016207:Cytokines; D007473:Ion Channels; D024101:Mitochondrial Proteins; D052638:Particulate Matter; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C029938:nickel sulfate; D009532:Nickel; D055372:AMP-Activated Protein Kinases