Induction of micronuclei in rat bone marrow and peripheral blood following acute and subchronic administration of azathioprine

Henderson, L.M.; Fedyk, Julia; Windebank, Samantha; Smith, Maurice R.

doi:10.1016/0165-1161(93)90019-v

Cited by 27 publications

(11 citation statements)

References 17 publications

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“…12 For some genotoxic compounds, there is a close relationship between the rate of MN and the expression of p53, 13 carcinogen, did not stimulate p53 expression in mouse fibroblast cells, 14 but it did induce MN in bone marrow and peripheral blood erythrocytes in rats. 15 In this study, p53 mRNA expression in the severe damage group (MN ≥ 4%) was lower than that of the mild damage group (MN < 4%), but p21 mRNA expression in the severe damage group was higher than that of the mild damage group. None of the differences in mRNA expression of p53, p21, and CCND1 between the two groups was significant.…”

Section: Discussioncontrasting

confidence: 74%

Messenger RNA Expression and Genetic Polymorphisms of Cell Cycle Control Genes and Chromosomal Aberrations in Chinese Vinyl Chloride Monomer-Exposed Workers

Qiu

Sun

Wang

et al. 2011

Journal of Occupational &Amp; Environmental Medicine

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Section: Discussioncontrasting

confidence: 74%

Messenger RNA Expression and Genetic Polymorphisms of Cell Cycle Control Genes and Chromosomal Aberrations in Chinese Vinyl Chloride Monomer-Exposed Workers

Qiu

Sun

Wang

et al. 2011

Journal of Occupational &Amp; Environmental Medicine

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“…Although the integration of the bone marrow micronucleus assay into general toxicology assays in rats has been reported [Henderson et al, 1993;Asanami et al, 1995;Garriott et al, 1995;Asanami and Shimono, 1996], the peripheral blood micronucleus assay is rarely performed in rats because circulating micronucleated erythrocytes are captured and destroyed in the rat spleen [Schlegel et al, 1982[Schlegel et al, , 1986Schlegel and Macgregor, 1984;Hayashi et al, 1992]. Despite this limitation, micronuclei were observed in the peripheral blood of rats by acridine orange supravital staining technique after treatment with mitomycin C (MMC), cyclophosphamide (CP), and benzo[a]pyrene (B[a]P) [Hayashi et al, 1992;Shimada et al, 1992].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the rodent micronucleus assay by a 28‐day treatment protocol: Summary of the 13th Collaborative Study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Environmental Mutagen Society of Japan (JEMS)–Mammalian Mutagenicity Study Group (MMS)

Hamada¹,

Sutou²,

Morita³

et al. 2001

Environ and Mol Mutagen

111

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To examine whether micronucleus tests can be incorporated into general toxicology assays, we performed micronucleus tests applying the treatment protocols typically used in such assays. In this 13th Collaborative Study of the CSGMT, both rats and mice were tested, although rats were used in the majority of the studies. Fifteen mutagens were tested in rats, mainly by oral (p.o.) administration. Micronucleus induction was evaluated 2, 3, and 4 days, and 1, 2, 3, and 28 days after the beginning of the treatment in the peripheral blood, and at 28 days in the bone marrow. Of the 15 chemicals that induced micronuclei in rats in short-term assays, two chemicals (1,2-dimethylhydrazine.2HCl and mitomycin C) were negative in all our experiments, possibly because of insufficient dose levels. The remaining 13 were positive within the estimated dose range of a general toxicology assay, suggesting the possibility of integrating the micronucleus assay into general toxicology assays. Three patterns were observed in micronucleus induction during the period of repeated treatment: (1) gradual increases in micronucleus frequency with sequential doses, (2) a peak at 3-5 days followed by gradual decreases in micronucleus frequency with sequential doses, and (3) a rapid increase in micronucleus frequency followed by a plateau. We evaluated factors that might have been involved in those patterns, such as the spleen function, target organ exposure, extramedullary hematopoiesis, hypothermia, and hypoxia. Another factor we considered was dosage. Because the dosages employed in a general toxicity assay are usually lower than those used in short-term micronucleus assays, this discrepancy was considered the greatest potential problem for integrating the micronucleus assay into general toxicology assays. Our results indicate that the integration of the micronucleus assay into a 28-day toxicological assay is feasible. To serve this purpose, blood samples collected 4 days after the beginning of treatment and blood and bone marrow samples collected at autopsy should be examined. Furthermore, although it is recognized that mice may be suitable for performing independent micronucleus assays, we propose that rats can provide biologically important and relevant information regarding potential chemical mutagens that can be evaluated under conditions used in the conduct of general toxicology studies.

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“…When the standard deviations of control groups are compared with data from manual assays, the deviations are lower than those in most reported studies with rats (13,20,35) but higher than in control groups of mice analysed with the flow cytometric technique (1,42). When the standard deviations of control groups are compared with data from manual assays, the deviations are lower than those in most reported studies with rats (13,20,35) but higher than in control groups of mice analysed with the flow cytometric technique (1,42).…”

Section: Resultsmentioning

confidence: 64%

Flow cytometric analysis of micronucleus induction in rat bone marrow polychromatic erythrocytes by 1,2;3,4-diepoxybutane, 3,4-epoxy-1-butene, and 1,2-epoxybutane-3,4-diol

Lähdetie

Grawé

1997

Cytometry

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Automation of the analysis of micronucleus induction with flow cytometry was developed by using mouse bone marrow or peripheral blood. In the present study, we report the use of flow cytometry for the identification and quantification of micronuclei (MN) induced in rat bone marrow polychromatic erythrocytes. Three metabolites of the industrial chemical 1,3‐butadiene, namely 1,2;3,4‐diepoxybutane (DEB), 3,4‐epoxy‐1‐butene (EB) and 1,2‐epoxybutane‐3,4‐diol (diol‐EB), were studied in addition to mitomycin C and cyclophosphamide, which served as positive controls. DEB showed a dose‐dependent increase in the frequency of MN, whereas EB was completely negative and diol‐EB only weakly positive at one dose level. The effect of the positive control compounds was observed 48 h after a single injection in a dose‐dependent manner. Flow cytometry was an effective method to quantitate bone marrow MN induction in the rat when density gradient separation of polychromatic erythrocytes is used. The results are compatible with the theory that oxidation of EB to the mutagenic metabolite DEB occurs at a low rate in rat bone marrow and that EB is detoxified by epoxide hydrolase and by conjugation with glutathione by glutathione transferase yielding nonmutagenic metabolites. Thus, the reported lack of MN induction by 1,3‐butadiene inhalation in rat bone marrow is explained. Cytometry 28:228–235, 1997. © 1997 Wiley‐Liss, Inc.

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Induction of micronuclei in rat bone marrow and peripheral blood following acute and subchronic administration of azathioprine

Cited by 27 publications

References 17 publications

Messenger RNA Expression and Genetic Polymorphisms of Cell Cycle Control Genes and Chromosomal Aberrations in Chinese Vinyl Chloride Monomer-Exposed Workers

Messenger RNA Expression and Genetic Polymorphisms of Cell Cycle Control Genes and Chromosomal Aberrations in Chinese Vinyl Chloride Monomer-Exposed Workers

Evaluation of the rodent micronucleus assay by a 28‐day treatment protocol: Summary of the 13th Collaborative Study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Environmental Mutagen Society of Japan (JEMS)–Mammalian Mutagenicity Study Group (MMS)

Flow cytometric analysis of micronucleus induction in rat bone marrow polychromatic erythrocytes by 1,2;3,4-diepoxybutane, 3,4-epoxy-1-butene, and 1,2-epoxybutane-3,4-diol

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