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Pro-oxidant Induced DNA Damage in Human Lymphoblastoid Cells: Homeostatic Mechanisms of Genotoxic Tolerance / A Seager; U.-K Shah; J Mikhail; B Nelson; B Marquis; S Doak; G Johnson; S Griffiths; P Carmichael; S Scott; A Scott; G Jenkins
Toxicological Sciences, Volume: 128, Start page: 387
Swansea University Author: Jenkins, Gareth
Oxidative stress contributes to many disease aetiologies including ageing, neurodegeneration, and cancer, partly through DNA damage induction (genotoxicity). Understanding the interactions of free radicals with DNA is fundamental to discern the mutation risks posed. In genetic toxicology, regulatory...
|Published in:||Toxicological Sciences|
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Oxidative stress contributes to many disease aetiologies including ageing, neurodegeneration, and cancer, partly through DNA damage induction (genotoxicity). Understanding the interactions of free radicals with DNA is fundamental to discern the mutation risks posed. In genetic toxicology, regulatory authorities view most genotoxins to exhibit a linear relationship between dose and mutagenic response. Yet, homeostatic mechanisms exist, including DNA repair, which allow cells to tolerate low levels of genotoxic exposure. 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 (H2O2), potassium bromate (KBrO3), and menadione, were examined for low dose-response curves in human lymphoblastoid cells. DNA repair and antioxidant capacity were assessed as possible threshold mechanisms. H2O2 and KBrO3, but not menadione, exhibited thresholded responses, containing a range of non-genotoxic low doses. Levels of the DNA glycosylase OGG1 were unchanged in response to pro-oxidant stress. DNA repair focussed 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 H2O2-treated AHH-1 cells reported accumulation of thymine glycol above the genotoxic threshold. Further, the H2O2 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”.
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Swansea University Medical School