Persistence of red blood cells with &lt;i&gt;Pig-a&lt;/i&gt; mutation in &lt;i&gt;p53&lt;/i&gt; knockout mice exposed to X-irradiation

Ohtani, S.; Ushiyama, Akira; Ootsuyama, Akira; Kunugita, Naoki

doi:10.2131/jts.39.7

Cited by 4 publications

(7 citation statements)

References 18 publications

(27 reference statements)

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“…In our study, we assessed mutations by the Pig-a gene mutation assay based on flow cytometry. There are only few studies exploring the mutagenic effect of ionising radiation by the Pig-a gene mutation assay192021 applying acute exposure with x-rays, and not chronic exposure with LDR γ-rays as done in the present study. Significant increases of mutation frequencies were detected in RET CD24− and RBC CD24− after 1 Gy total dose (C57BL/6J mice)2021 and in RBC CD24− after 2 Gy total dose (F344 rats)19 of acute x-ray exposure.…”

Section: Discussionmentioning

confidence: 99%

Gamma radiation at a human relevant low dose rate is genotoxic in mice

Graupner

Eide

Instanes

et al. 2016

Sci Rep

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Even today, 70 years after Hiroshima and accidents like in Chernobyl and Fukushima, we still have limited knowledge about the health effects of low dose rate (LDR) radiation. Despite their human relevance after occupational and accidental exposure, only few animal studies on the genotoxic effects of chronic LDR radiation have been performed. Selenium (Se) is involved in oxidative stress defence, protecting DNA and other biomolecules from reactive oxygen species (ROS). It is hypothesised that Se deficiency, as it occurs in several parts of the world, may aggravate harmful effects of ROS-inducing stressors such as ionising radiation. We performed a study in the newly established LDR-facility Figaro on the combined effects of Se deprivation and LDR γ exposure in DNA repair knockout mice (Ogg1−/−) and control animals (Ogg1+/−). Genotoxic effects were seen after continuous radiation (1.4 mGy/h) for 45 days. Chromosomal damage (micronucleus), phenotypic mutations (Pig-a gene mutation of RBCCD24−) and DNA lesions (single strand breaks/alkali labile sites) were significantly increased in blood cells of irradiated animals, covering three types of genotoxic activity. This study demonstrates that chronic LDR γ radiation is genotoxic in an exposure scenario realistic for humans, supporting the hypothesis that even LDR γ radiation may induce cancer.

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Section: Discussionmentioning

confidence: 99%

Gamma radiation at a human relevant low dose rate is genotoxic in mice

Graupner

Eide

Instanes

et al. 2016

Sci Rep

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“…DNA lesions followed by subsequent mutations have the potential to contribute to carcinogenesis. To our knowledge, only two other groups have applied the Pig‐a gene mutation assay as a tool to measure ionising radiation effects (Ohtani et al, ; Bhalli et al, ; Ohtani et al, ).…”

Section: Introductionmentioning

confidence: 99%

Genotoxic effects of high dose rate X‐ray and low dose rate gamma radiation in Apc^Min/+ mice

Graupner

Eide

Brede

et al. 2017

Environ and Mol Mutagen

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Risk estimates for radiation‐induced cancer in humans are based on epidemiological data largely drawn from the Japanese atomic bomb survivor studies, which received an acute high dose rate (HDR) ionising radiation. Limited knowledge exists about the effects of chronic low dose rate (LDR) exposure, particularly with respect to the application of the dose and dose rate effectiveness factor. As part of a study to investigate the development of colon cancer following chronic LDR vs. acute HDR radiation, this study presents the results of genotoxic effects in blood of exposed mice. CBAB6 F1 Apc+/+ (wild type) and ApcMin/+ mice were chronically exposed to estimated whole body absorbed doses of 1.7 or 3.2 Gy 60Co‐γ‐rays at a LDR (2.2 mGy h−1) or acutely exposed to 2.6 Gy HDR X‐rays (1.3 Gy min−1). Genotoxic endpoints assessed in blood included chromosomal damage (flow cytometry based micronuclei (MN) assay), mutation analyses (Pig‐a gene mutation assay), and levels of DNA lesions (Comet assay, single‐strand breaks (ssb), alkali labile sites (als), oxidized DNA bases). Ionising radiation (ca. 3 Gy) induced genotoxic effects dependent on the dose rate. Chromosomal aberrations (MN assay) increased 3‐ and 10‐fold after chronic LDR and acute HDR, respectively. Phenotypic mutation frequencies as well as DNA lesions (ssb/als) were modulated after acute HDR but not after chronic LDR. The ApcMin/+ genotype did not influence the outcome in any of the investigated endpoints. The results herein will add to the scant data available on genotoxic effects following chronic LDR of ionising radiation. Environ. Mol. Mutagen. 58:560–569, 2017. © 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society

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“…Mutagenic effects of ionizing radiation such as X‐rays and gamma irradiation have been studied and provide valuable information concerning timing of mutant induction and elimination in mice, as well as responses after acute versus protracted/chronic exposure to mutagens. Moreover, in contrast to many chemicals, ionizing radiation does not depend on metabolic activation to exert its effects.…”

Section: Pig‐a In Micementioning

confidence: 99%

“…There were marked interindividual differences, both in the magnitude of the maximal response and in time until maximum response was evident. This study was followed up by investigations of the role of p53 for X‐ray‐induced Pig‐a mutants, showing that the persistence of mutated RBCs was slower in p53 −/− mice than in wild‐type mice and that Pig‐a mutations increased with increasing age of p53 −/− mice . These studies used acute high dose rates (0.52 Gy/min) of X‐rays.…”

Section: Pig‐a In Micementioning

confidence: 99%

“…Mice exhibiting different deficiencies in DNA repair proteins involved in protection of the genome from oxidized DNA have been studied [, Rolseth et al ., unpublished]. The DNA repair proteins investigated are involved in base excision repair eliminating oxidized DNA damage and comprise 8‐oxoguanine DNA glycosylase (Ogg1), the MutY DNA glycosylase (MutY) and three endonuclease VIII‐like DNA glycosylases (Neil1, Neil2 and Neil3) as well as the tumour protein p53 (p53).…”

Section: Usefulness In Basic Sciencementioning

confidence: 99%

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The Pig‐a Gene Mutation Assay in Mice and Human Cells: A Review

Olsen

Dertinger

Krüger

et al. 2017

Basic Clin Pharma Tox

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This MiniReview describes the principle of mutation assays based on the endogenous Pig-a gene and summarizes results for two species of toxicological interest, mice and human beings. The work summarized here largely avoids rat-based studies, as are summarized elsewhere. The Pig-a gene mutation assay has emerged as a valuable tool for quantifying in vivo and in vitro mutational events. The Pig-a locus is located at the X-chromosome, giving the advantage that one inactivated allele can give rise to a mutated phenotype, detectable by multicolour flow cytometry. For in vivo studies, only minute blood volumes are required, making it easily incorporated into ongoing studies or experiments with limited biological materials. Low blood volumes also allow individuals to serve as their own controls, providing temporal information of the mutagenic process, and/or outcome of intervention. These characteristics make it a promising exposure marker. To date, the Pig-a gene mutation assay has been most commonly performed in rats, while reports regarding its usefulness in other species are accumulating. Besides its applicability to in vivo studies, it holds promise for genotoxicity testing using cultured cells, as shown in recent studies. In addition to safety assessment roles, it is becoming a valuable tool in basic research to identify mutagenic effects of different interventions or to understand implications of various gene defects by investigating modified mouse models or cell systems. Human blood-based assays are also being developed that may be able to identify genotoxic environmental exposures, treatment- and lifestyle-related factors or endogenous host factors that contribute to mutagenesis.

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Persistence of red blood cells with <i>Pig-a</i> mutation in <i>p53</i> knockout mice exposed to X-irradiation

Cited by 4 publications

References 18 publications

Gamma radiation at a human relevant low dose rate is genotoxic in mice

Gamma radiation at a human relevant low dose rate is genotoxic in mice

Genotoxic effects of high dose rate X‐ray and low dose rate gamma radiation in Apc^Min/+ mice

The Pig‐a Gene Mutation Assay in Mice and Human Cells: A Review

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Persistence of red blood cells with <i>Pig-a</i> mutation in <i>p53</i> knockout mice exposed to X-irradiation

Cited by 4 publications

References 18 publications

Gamma radiation at a human relevant low dose rate is genotoxic in mice

Gamma radiation at a human relevant low dose rate is genotoxic in mice

Genotoxic effects of high dose rate X‐ray and low dose rate gamma radiation in ApcMin/+ mice

The Pig‐a Gene Mutation Assay in Mice and Human Cells: A Review

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Product

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Genotoxic effects of high dose rate X‐ray and low dose rate gamma radiation in Apc^Min/+ mice