Accumulation and persistence of Pig-A mutant peripheral red blood cells following treatment of rats with single and split doses of N-ethyl-N-nitrosourea

Miura, Daisuke; Dobrovolsky, Vasily N.; Kimoto, Tsunenobu; Kasahara, Yoshinori; Heflich, Robert H.

doi:10.1016/j.mrgentox.2009.05.014

Cited by 97 publications

(101 citation statements)

References 27 publications

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“…CD59-negative mutants have been shown to increase in number through the proliferation of mutated erythrocyte precursors and/or stem cells after the single administration of several mutagens (10,25). In contrast, in this study, the increase in mutation frequency during repeated MDA dosing was found to be stable in the RBC Pig-a assay and transient in the PIGRET assay in each 40 mg/kg/day group.…”

contrasting

confidence: 74%

“…Both Pig-a gene mutation assays can detect these mutated cells using flow cytometry and are thought to be simpler than the traditional in vivo mutation assays because it requires minor sample volume and a shorter experimental period with an uncomplicated procedure. The important property of the assays is to detect cumulative effect of the treatment (10), and this specific property allows the assays to be integrated into the general toxicity tests, so that gene mutation can be evaluated without using the need to use additional animals. Therefore, the RBC Pig-a and PIGRET assays have been validated for their ability to determine the carcinogenicity of a variety of chemicals in red blood cells (11,12); However, additional data must be accumulated to further substantiate the validity of these assays.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation for a Mutagenicity of 4,4^|^prime;-Methylenedianiline on Hematopoietic Cells by a Pig-a Gene Mutation Assay in Rats

Sanada

Okamoto

Ohsumi

et al. 2014

Genes and Environment

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The Pig-a gene is involved in the synthesis of glycosylphosphatidylinositol (GPI) anchors. Pig-a gene mutations can be detected by identifying the presence of CD59, the GPI anchor protein, on the surface of erythrocytes (RBC Pig-a assay) and reticulocytes (PIGRET assay) and can be identified using flow cytometry. The usefulness of these Pig-a gene mutation assays has been confirmed in multilaboratory trials with referenced mutagens. Although 4, 4′ -methylenedianiline (MDA) is an aromatic amine and has been identified as a potent hepatic carcinogen, in vivo micronucleus tests for MDA in hematopoietic cells determined that it was negative to weakly positive for genotoxicity. In the present study, we examined the mutagenicity of MDA in the peripheral blood of rats after 1-and 28-day MDA dosing using the Pig-a gene mutation assays. We also examined the utility of the RBC Pig-a and PIGRET assays. No changes in mutation frequency were observed after one-day MDA administration. Repeated dosing caused a moderate increase in mutation frequency compared to vehicle control at days 14 and 28, as measured by the RBC Pig-a assay and at day 14 by the PIGRET assay. The highest mutation frequency was found on days 7 and 14 by the PIGRET and RBC Pig-a assays, respectively.In this study, we detected the mutagenicity of MDA in peripheral blood samples using gene mutation assays and judged to be positive for the MDA mutagenicity since a significant increase in mutation frequency was observed at high dose. These assays are expected to be easily integrated into general toxicity tests and to be combined with existing genotoxicity studies.

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contrasting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Evaluation for a Mutagenicity of 4,4^|^prime;-Methylenedianiline on Hematopoietic Cells by a Pig-a Gene Mutation Assay in Rats

Sanada

Okamoto

Ohsumi

et al. 2014

Genes and Environment

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“…With this method, we need no transgenic animals to test in vivo genotoxicity, but need only 1-2 mL peripheral blood (5,6). Additionally, long-term, accumulated in vivo genotoxic eŠects could be evaluated (9).…”

Section: Introductionmentioning

confidence: 99%

Fullerene (C60) Is Negative in the In Vivo Pig-A Gene Mutation Assay

Horibata

Ukai

Naoki

et al. 2011

Genes and Environment

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Carbon nanoparticles, such as carbon nanotubes and fullerene (C 60 ), are potential candidates as leading substances in nanotechnologicalˆelds, but little is known about their safety. Here we examined in vivo genotoxicity of C 60 , by performing the Pig-A gene mutation assay in the peripheral blood of male C57BL/6Cr mice. Mice were given single intraperitoneal injection of 3 mg of C 60 particles in 0.5 mL suspension containing 0.1%-Tween80-saline. As a positive control for the Pig-A gene mutation assay, mice were given a single oral administration of N-nitroso-Nethylurea. At 2 and 8 weeks after treatments, we analyzed CD24-negative and -positive red blood cells in peripheral blood and calculated Pig-A mutant frequencies. As a result, we detected no signiˆcant diŠerences in the mutant frequencies between C 60 treated and non-treated mice, indicating that C 60 is negative for genotoxicity in vivo in the limited target tissues assessed in this study. For the full assessment, we need comprehensive whole body survey on the genotoxicity of C 60 .

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“…Les cellules GPI-déficientes qui circulent apparaissent donc après un délai appelé temps d'expression phénotypique qui correspond au temps nécessaire pour la production des cellules et leur différenciation en cellules matures circulantes [20,21]. L'expression ubiquitaire du gène PIG-A rend le test applicable à l'ensemble des cellules eucaryotes mais les lignées érythrocytaire et granulocytaire sont principalement étudiées dans la littérature (Tableau I).…”

Section: Populations Cellulaires Sanguines Circulantesunclassified