Simultaneous use of erythropoietin and prior bleeding enhances the sensitivity of the peripheral blood micronucleus assay

Mughal, Amreen; Vikram, Ajit; Kushwaha, Sapana; Jena, Gopabandhu

doi:10.1093/mutage/geq099

Cited by 7 publications

(3 citation statements)

References 45 publications

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“…Other studies suggest that AZT leads to an active proliferation and specific downregulation of transcription factors in the bone marrow (Olivero, 2007). In peripheral blood, the number of MN-RETs starts to increase from day 2 onward, which is in line with previous studies that have been performed in order to assess the time course of MN induction in RET (Mughal et al, 2010). With AZT being eliminated quickly from the body, the induced MN-RETs are expected to decrease within a few days because only "penultimate" erythroblasts prior to their final cell division can give rise to MN-RETs.…”

Section: Discussionsupporting

confidence: 87%

Assessment of the Genotoxic Potential of Azidothymidine in the Comet, Micronucleus, and Pig-a Assay

Guérard

Koenig

Festag

et al. 2013

Toxicological Sciences

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The genotoxic potential of azidothymidine (Zidovudine, AZT), chosen as a model compound for nucleotide analogs, was comprehensively assessed in vivo for gene mutation, clastogenicity, and DNA breakage endpoints. Male Wistar rats were treated by oral gavage over 7 days with AZT at dose levels of 2×0 (control), 2×250, 2×500, and 2×1000mg/kg/day with a final single dose given on day 8. DNA damage was then evaluated with the comet assay in liver, stomach, and peripheral blood and with the micronucleus test in bone marrow and peripheral blood (by flow cytometry) in the same animals. After a treatment-free period of upto 42 days, the Pig-a gene mutation assay was performed in peripheral blood of the high-dose animals. In the comet assay as well as the micronucleus test, AZT caused a considerable dose-dependent increase in DNA damage in all tissues evaluated and was highly cytotoxic to bone marrow and peripheral blood cells. These data are well in line with published results. Surprisingly, AZT did not significantly increase the number of Pig-a mutant cells. We speculate that two factors likely contributed to this negative result: a predominance of large deletions caused by AZT, and the relatively low statistical power of the first-generation scoring method used for this study.

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Section: Discussionsupporting

confidence: 87%

Assessment of the Genotoxic Potential of Azidothymidine in the Comet, Micronucleus, and Pig-a Assay

Guérard

Koenig

Festag

et al. 2013

Toxicological Sciences

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“…of mutant RETs × 10 -6 Day 23 2 × 0 3.51 ± 0.68 0.5 ± 1.0 0.5 ± 1.0 2 × 1000 3.69 ± 0.57 1. bone marrow (Olivero, 2007). In peripheral blood, the number of MN-RETs starts to increase from day 2 onward, which is in line with previous studies that have been performed in order to assess the time course of MN induction in RET (Mughal et al, 2010). With AZT being eliminated quickly from the body, the induced MN-RETs are expected to decrease within a few days because only "penultimate" erythroblasts prior to their final cell division can give rise to MN-RETs.…”

Section: Discussionsupporting

confidence: 82%

Drug Discovery Toxicology

Will¹,

McDuffie²,

Olaharski³

et al. 2016

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The genotoxic potential of azidothymidine (Zidovudine, AZT), chosen as a model compound for nucleotide analogs, was comprehensively assessed in vivo for gene mutation, clastogenicity, and DNA breakage endpoints. Male Wistar rats were treated by oral gavage over 7 days with AZT at dose levels of 2 × 0 (control), 2 × 250, 2 × 500, and 2 × 1000 mg/kg/day with a final single dose given on day 8. DNA damage was then evaluated with the comet assay in liver, stomach, and peripheral blood and with the micronucleus test in bone marrow and peripheral blood (by flow cytometry) in the same animals. After a treatment-free period of upto 42 days, the Pig-a gene mutation assay was performed in peripheral blood of the high-dose animals. In the comet assay as well as the micronucleus test, AZT caused a considerable dose-dependent increase in DNA damage in all tissues evaluated and was highly cytotoxic to bone marrow and peripheral blood cells. These data are well in line with published results. Surprisingly, AZT did not significantly increase the number of Pig-a mutant cells. We speculate that two factors likely contributed to this negative result: a predominance of large deletions caused by AZT, and the relatively low statistical power of the first-generation scoring method used for this study.

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“…Prior bleeding has been shown to enhance the sensitivity on the micronucleus test in rats 18 and mice 19 and simultaneous use of both prior bleeding and unspecified EPO is reported to have the same effect in young (26 days) Sprague-Dawley rats. 20 Because age is also known to influence the sensitivity of the micronucleus assay in both peripheral blood and bone marrow in the rat, 21 the objective of this study was to clarify any effect of bleeding on the frequency of MIEs in the 10-week old Han Wistar rats routinely used in this laboratory. Although blood withdrawal up to the maximum allowed by the Home Office licence did not increase MIE frequency, endogenous levels of EPO were increased to measurable levels and, because of the action of EPO, it is possible that this may enhance the response to DNA damaging agents.…”

Section: Discussionmentioning

confidence: 99%