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Publications (5)9.17 Total impact

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    ABSTRACT: The liver micronucleus test is an important method to detect in vivo genotoxicants, especially those that require metabolic activation for their genotoxicity. We have already reported that structural or numerical chromosome aberration inducers have to be given before or after partial hepatectomy, respectively, to detect their genotoxicity in the liver of rats. In the present study, we assessed a twice dosing regimen, in which the genotoxicant is dosed both before and after partial hepatectomy, using the four chromosome aberration inducers used in the previous study. Two structural chromosome aberration inducers (diethylnitrosamine and 1,2-dimethylhydrazine) and two numerical chromosome aberration inducers (colchicine and carbendazim) were used. The genotoxicant was administered to 8-week old male F344 rats one day before and again one day after the partial hepatectomy and hepatocytes were isolated 3 days after second dosing (4 days after the partial hepatectomy). As a result, all genotoxicants (structural or numerical chromosome aberration inducers) caused a dose-dependent statistically significant increase in the incidence of micronucleated hepatocytes when given both before and after partial hepatectomy. No marked difference was observed in general toxicity, relative liver weight and cell classification between single dosing regimens and twice dosing regimen of the genotoxicants. These results confirm that the twice dosing regimen, in which the test compound is dosed both before and after partial hepatectomy, can detect in vivo induction of micronucleated hepatocytes by structural or numerical chromosome aberration inducers qualitatively similar to their appropriate regimen in which the test compound is administered either before or after partial hepatectomy. Copyright © 2015 Elsevier B.V. All rights reserved.
    04/2015; 782:18-23. DOI:10.1016/j.mrgentox.2015.03.008
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    ABSTRACT: In the view of animal welfare considerations, we investigated the suitability of modifying the rat liver micronucleus test with partial hepatectomy to include administration of an analgesic drug to minimize pain and distress as much as possible. The effects of the analgesic, buprenorphine, on the genotoxicity evaluation of structural chromosome aberration inducers (cyclophosphamide, diethylnitrosamine and 1,2-dimethylhydrazine) and numerical chromosome aberration inducers (colchicine and carbendazim) were examined. The genotoxicants were given orally to 8-week-old male F344 rats a day before or after partial hepatectomy and hepatocytes were isolated 4 days after the partial hepatectomy. Buprenorphine was injected subcutaneously twice a day with at least a 6-hr interval for 2 days from just after partial hepatectomy. As results, buprenorphine caused neither change in clinical signs (except for one animal death) nor increase in the incidence of micronucleated hepatocytes of vehicle treated animals. In the case of concomitant treatment of buprenorphine and a genotoxicant, one out of 8 animals died in each group given buprenorphine with cyclophosphamide, carbendazim or colchicine (lower dose level only). Slight changes in clinical signs were noted in the group given buprenorphine with cyclophosphamide or carbendazim. A statistically significant increase in the incidence of micronucleated hepatocytes was obtained in concomitant treatment of buprenorphine and genotoxicant compared with genotoxicant alone for 1,2-dimethylhydrazine, colchicine and carbendazim. It is concluded that use of buprenorphine as an analgesic drug to minimize pain and distress for rats that are given partial hepatectomy is not appropriate under the present experimental conditions, because it could enhance the general toxicity and genotoxicity of the test chemical.
    The Journal of Toxicological Sciences 01/2015; 40(1):109-14. DOI:10.2131/jts.40.109 · 1.38 Impact Factor
  • Genes and Environment 01/2014; DOI:10.3123/jemsge.2014.022
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    ABSTRACT: The liver micronucleus test in rats with partial hepatectomy is a useful method to detect pro-clastogens such as diethylnitrosamine, the active metabolites of which do not reach the bone marrow due to their short lifespan. We have already reported that structural or numerical chromosome aberration inducers should be given before or after partial hepatectomy, respectively, to detect genotoxicity in the liver of rats. In the present study, we found that the percentage of binucleated cells in the liver from naive male rats is approximately 60% of that in female rats, which suggests a gender difference in the response to chromosome aberration inducers. Therefore, we investigated the responses to structural chromosome aberration inducers (diethylnitrosamine and 1,2-dimethylhydrazine) and numerical chromosome aberration inducers (colchicine and carbendazim) in male and female rats. The chemicals were given to 8-week-old male and female F344 rats a day before or after partial hepatectomy and hepatocytes were isolated 4 days after the partial hepatectomy. As the results, diethylnitrosamine and 1,2-dimethylhydrazine produced a significant increase in the frequency of micronucleated hepatocytes in both genders and the responses were comparable. In the case of colchicine and carbendazim, higher frequencies in the micronucleated hepatocytes were obtained in males than in females. Taken together, the response to chromosome aberration inducers in male rats was equal to or stronger than that in female rats. It seems that the use of only male rats in the liver micronucleus test is sufficient, unless existing data indicate a toxicologically meaningful gender difference in rats.
    Toxicology Letters 09/2012; 214(3):296-300. DOI:10.1016/j.toxlet.2012.09.003 · 3.36 Impact Factor
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    ABSTRACT: The liver micronucleus test is an important method to detect pro-mutagens such as active metabolites not reaching bone marrow due to their short lifespan. We have already reported that dosing of the test compound after partial hepatectomy (PH) is essential to detect genotoxicity of numerical chromosome aberration inducers in mice [Mutat. Res. 632 (2007) 89-98]. In naive animals, the proportion of binucleated cells in rats is less than half of that in mice, which suggests a species difference in the response to chromosome aberration inducers. In the present study, we investigated the responses to structural and numerical chromosome aberration inducers in the rat liver micronucleus test. Two structural chromosome aberretion inducers (diethylnitrosamine and 1,2-dimethylhydrazine) and two numerical chromosome aberration inducers (colchicine and carbendazim) were used in the present study. PH was performed a day before or after the dosing of the test compound in 8-week old male F344 rats and hepatocytes were isolated 4 days after the PH. As a result, diethylnitrosamine and 1,2-dimethylhydrazine, structural chromosome aberration inducers, exhibited significant increase in the incidence of micronucleated hepatocyte (MNH) when given either before and after PH. Colchicine and carbendazim, numerical chromosome aberration inducers, did not result in any toxicologically significant increase in MNH frequency when given before PH, while they exhibited MNH induction when given after PH. It is confirmed that dosing after PH is essential in order to detect genotoxicity of numerical chromosome aberration inducers in rats as well as in mice. Regarding the species difference, a different temporal response to colchicine was identified. Colchicine increased the incidence of MNH 4 days after PH in rats, although such induction in mice was observed 8-10 days after PH.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 04/2012; 747(1):98-103. DOI:10.1016/j.mrgentox.2012.04.007 · 4.44 Impact Factor