title: Mitochondria-derived reactive intermediate species mediate asbestos-induced genotoxicity and oxidative stress-responsive signaling pathways.
abstract: BACKGROUND
  The incidence of asbestos-induced human cancers is increasing worldwide, and considerable evidence suggests that reactive oxygen species (ROS) are important mediators of these diseases. Our previous studies suggested that mitochondria might be involved in the initiation of oxidative stress in asbestos-exposed mammalian cells.
  
  
  OBJECTIVE
  We investigated whether mitochondria are a potential cytoplasmic target of asbestos using a mitochondrial DNA-depleted (ρ(0)) human small airway epithelial (SAE) cell model: ρ(0) SAE cells lack the capacity to produce mitochondrial ROS.
  
  
  METHODS
  We examined nuclear DNA damage, micronuclei (MN), intracellular ROS production, and the expression of inflammation-related nuclear genes in both parental and ρ(0) SAE cells in response to asbestos treatment.
  
  
  RESULTS
  Asbestos induced a dose-dependent increase in nuclear DNA oxidative damage and MN in SAE cells. Furthermore, there was a significant increase in intracellular oxidant production and activation of genes involved in nuclear factor κB and proinflammatory signaling pathways in SAE cells. In contrast, the effects of asbestos were minimal in ρ(0) SAE cells.
  
  
  CONCLUSIONS
  Mitochondria are a major cytoplasmic target of asbestos. Asbestos may initiate mitochondria-associated ROS, which mediate asbestos-induced nuclear mutagenic events and inflammatory signaling pathways in exposed cells. These data provide new insights into the molecular mechanisms of asbestos-induced genotoxicity.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.
authors.forename: Sarah X L
authors.initials: SX
authors.lastname: Huang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Partridge
authors.forename: Shanaz A
authors.initials: SA
authors.lastname: Ghandhi
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.forename: Sally A
authors.initials: SA
authors.lastname: Amundson
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000704:Analysis of Variance; D001194:Asbestos / Q000009:adverse effects*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D015162:Micronucleus Tests; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012137:Respiratory System / Q000166:cytology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017382:Reactive Oxygen Species; D001194:Asbestos; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine