Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8456414 | Mutation Research/Genetic Toxicology and Environmental Mutagenesis | 2015 | 7 Pages |
Abstract
The liver micronucleus (MN) assay is useful for predicting genotoxic rodent hepatocarcinogenicity. We have recently established the repeated-dose liver MN (RDLMN) assay in rats for integration into general toxicity studies. To investigate the effectiveness of the RDLMN assay, the genotoxic rodent hepatocarcinogen, monocrotaline (MCT), was administered by oral gavage to 6-week old male rats once daily for 14 days at 0.5 and 1.5Â mg/kg/day, and for 28 days at 0.15, 0.5, 1.5, 3.75, 7.5 and 15Â mg/kg/day. Then, MN induction was measured in the liver and bone marrow (BM), and histopathological hepatotoxicity was examined. Additionally, in order to evaluate the effects of repeated dosing periods on MN inducibility, a double-dose examination of MCT at doses of 15, 30 and 60Â mg/kg/day in juvenile (26-days old) and young adult (7-weeks old) rats was also conducted, as an acute dose MN assay. The peripheral blood (PB) and liver were sampled at 48Â h and 4 days after the second dosing, respectively. In the repeated-dose MN assay, MCT produced a positive result in the liver at a non-hepatotoxic lower dose level, but not in the BM at any dose level. In contrast, in the double-dose MN assay, MCT showed a negative result in the young adult rat livers, although it gave positive responses in the livers of juvenile rats and in the PB with both age groups. The maximum dose used in the repeated-dose assay was considerably lower than that used in the acute dose assay. These results suggest that a repeated dosing regimen is more suitable for the liver MN assay using young adult rats than an acute dose regimen, and the RDLMN assay might be capable of detecting genotoxic rodent hepatocarcinogens at dose levels that are typically undetectable in BM MN assays.
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Authors
Rie Takashima, Hironao Takasawa, Yumi Wako, Katsuaki Yasunaga, Akiko Hattori, Masayoshi Kawabata, Kiyoko Nakadate, Munehiro Nakagawa, Shuichi Hamada,