title: Mechanism of genotoxicity induced by targeted cytoplasmic irradiation.
abstract: BACKGROUND
  Direct damage to DNA is generally accepted as the main initiator of mutation and cancer induced by environmental carcinogens or ionising radiation. However, there is accumulating evidence suggesting that extracellular/extranuclear targets may also have a key role in mediating the genotoxic effects of ionising radiation. As the possibility of a particle traversal through the cytoplasm is much higher than through the nuclei in environmental radiation exposure, the contribution to genotoxic damage from cytoplasmic irradiation should not be ignored in radiation risk estimation. Although targeted cytoplasmic irradiation has been shown to induce mutations in mammalian cells, the precise mechanism(s) underlying the mutagenic process is largely unknown.
  
  
  METHODS
  A microbeam that can target the cytoplasm of cells with high precision was used to study mechanisms involved in mediating the genotoxic effects in irradiated human-hamster hybrid (A(L)) cells.
  
  
  RESULTS
  Targeted cytoplasmic irradiation induces oxidative DNA damages and reactive nitrogen species (RNS) in A(L) cells. Lipid peroxidation, as determined by the induction of 4-hydroxynonenal was enhanced in irradiated cells, which could be suppressed by butylated hydroxyl toluene treatment. Moreover, cytoplasmic irradiation of A(L) cells increased expression of cyclooxygenase-2 (COX-2) and activation of extracellular signal-related kinase (ERK) pathway.
  
  
  CONCLUSIONS
  We herein proposed a possible signalling pathway involving reactive oxygen/nitrogen species and COX-2 in the cytoplasmic irradiation-induced genotoxicity effect.
authors.affiliation: Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hong
authors.forename: A
authors.initials: A
authors.lastname: Xu
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.forename: G
authors.initials: G
authors.lastname: Randers-Pehrson
authors.forename: R M
authors.initials: RM
authors.lastname: Santella
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.forename: T K
authors.initials: TK
authors.lastname: Hei
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003593:Cytoplasm / Q000528:radiation effects*; D004249:DNA Damage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells / Q000528:radiation effects / Q000648:ultrastructure; D015227:Lipid Peroxidation / Q000528:radiation effects; D009152:Mutagenicity Tests; D018384:Oxidative Stress / Q000528:radiation effects; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases