title: Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance.
abstract: Oxidative stress contributes to many disease etiologies including ageing, neurodegeneration, and cancer, partly through DNA  damage induction (genotoxicity). Understanding the i nteractions of free radicals with DNA is fundamental to discern mutation risks. In genetic toxicology, regulatory authorities consider that most genotoxins exhibit a linear relationship between dose and mutagenic  response. Yet, homeostatic mechanisms, including DNA  repair, that allow cells to tolerate low levels of genotoxic exposure exist. Acceptance of thresholds for genotoxicity has widespread consequences in terms of understanding cancer risk and regulating human exposure to chemicals/drugs. Three pro-oxidant chemicals, hydrogen peroxide (H(2)O(2)), potassium bromate (KBrO(3)), and menadione, were examined for low dose-response curves in human lymphoblastoid cells. DNA repair and antioxidant capacity were assessed as possible threshold mechanisms. H(2)O(2) and KBrO(3), but not menadione, exhibited thresholded responses, containing a range of nongenotoxic low doses. Levels of the DNA glycosylase 8-oxoguanine glycosylase  were unchanged in response to pro- oxidant stress. DNA repair-focused gene expression arrays reported changes in ATM and BRCA1, involved in double-strand break repair, in response to low-dose pro-oxidant exposure; however, these alterations were not substantiated at the protein level. Determination of oxidatively induced DNA damage in H(2)O(2)-treated AHH-1 cells reported accumulation of thymine glycol above the genotoxic threshold. Further, the H(2)O(2) dose-response curve was shifted by modulating the antioxidant glutathione. Hence, observed pro- oxidant thresholds were due to protective capacities of base excision repair enzymes and antioxidants against DNA damage, highlighting the importance of homeostatic mechanisms in "genotoxic tolerance."
authors.affiliation: DNA Damage Research Group, Institute of Life Science, College of Medicine, Swansea University, SA2 8PP, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Seager
authors.forename: Ume-Kulsoom
authors.initials: UK
authors.lastname: Shah
authors.forename: Jane M
authors.initials: JM
authors.lastname: Mikhail
authors.forename: Bryant C
authors.initials: BC
authors.lastname: Nelson
authors.forename: Bryce J
authors.initials: BJ
authors.lastname: Marquis
authors.forename: Shareen H
authors.initials: SH
authors.lastname: Doak
authors.forename: George E
authors.initials: GE
authors.lastname: Johnson
authors.forename: Sioned M
authors.initials: SM
authors.lastname: Griffiths
authors.forename: Paul L
authors.initials: PL
authors.lastname: Carmichael
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Scott
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Scott
authors.forename: Gareth J S
authors.initials: GJ
authors.lastname: Jenkins
mesh_terms: D015153:Blotting, Western; D001959:Bromates / Q000633:toxicity; D002460:Cell Line; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000494:pharmacology; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000633:toxicity*; D024483:Vitamin K 3 / Q000633:toxicity
chemical_list: D001959:Bromates; D009153:Mutagens; D017382:Reactive Oxygen Species; C019536:potassium bromate; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D005978:Glutathione