title: Micronucleus induction in rat liver and bone marrow by acute vs. repeat doses of the genotoxic hepatocarcinogen monocrotaline.
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 1.5mg/kg/day, and for 28 days at 0.15, 0.5, 1.5, 3.75, 7.5 and 15mg/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 60mg/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 48h 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.
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan. Electronic address: Takashima.Rie@ma.medience.co.jp.
authors.forename: Rie
authors.initials: R
authors.lastname: Takashima
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Takasawa
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Wako
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Yasunaga
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hattori
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kawabata
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Nakadate
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Munehiro
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hamada
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002869:Chromosome Aberrations / Q000187:drug effects; D003299:Cooperative Behavior; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007564:Japan; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D015162:Micronucleus Tests; D016686:Monocrotaline / Q000633:toxicity*; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012156:Reticulocytes / Q000187:drug effects; D012957:Societies, Pharmaceutical
chemical_list: D002273:Carcinogens; D016686:Monocrotaline
keywords: Genotoxic hepatocarcinogens; Micronucleus assay; Monocrotaline; Repeated-dose liver genotoxicity assay