title: Repeated dose liver and gastrointestinal tract micronucleus assays using N-methyl-N'-nitro-N-nitrosoguanidine in young adult rats.
abstract: N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) is a direct-acting mutagen that induces tumors in the glandular stomach, but not in the liver or colon, of rats after oral administration. To evaluate the performance of repeated dose liver and gastrointestinal tract micronucleus (MN) assays in young adult rats, MNNG was administered by oral gavage to male CD (SD) rats aged 6 weeks at doses of 0 (vehicle; 2.5% DMSO aqueous solution), 3.125, 6.25, 12.5, and 25mg/kg/day once daily for 14 and 28 days, and the MN frequencies were examined in the hepatocytes, glandular stomach cells, and colonic cells. The MN induction in immature erythrocytes in the bone marrow of these animals was also simultaneously evaluated. The frequencies of micronucleated (MNed) glandular stomach cells were significantly increased in all MNNG treatment groups in a dose-dependent manner in both repeated dose studies. In contrast, the frequencies of MNed hepatocytes and colonic cells were not significantly increased compared to the vehicle control. In the bone marrow, a small but significant increase in the frequency of MNed immature erythrocytes was observed only at the highest dose in the 28-day study. Since a clear positive result in the glandular stomach agrees with the tissue specificity of tumor induction by this chemical, the MN assay with the glandular stomach, which is a direct contact site with high concentrations of test substances administered by oral gavage, may be useful for detecting genotoxic compounds that are short-lived in vivo, such as MNNG.
authors.affiliation: Suntory Business Expert Limited, 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8503, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Takayanagi
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: Kazufumi
authors.initials: K
authors.lastname: Kawasako
authors.affiliation: Suntory Business Expert Limited, 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8503, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Hori
authors.affiliation: Suntory Business Expert Limited, 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8503, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Fujii
authors.affiliation: Yakult Honsha Co., Ltd., 1796 Yaho, Kunitachi-shi, Tokyo 186-8650, Japan. Electronic address: waka-ooyama@yakult.co.jp.
authors.forename: Wakako
authors.initials: W
authors.lastname: Ohyama
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity*; D002869:Chromosome Aberrations / Q000187:drug effects; D003106:Colon / Q000187:drug effects; D003299:Cooperative Behavior; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007564:Japan; D008099:Liver / Q000187:drug effects; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000633:toxicity*; D015162:Micronucleus Tests; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012156:Reticulocytes / Q000187:drug effects* / Q000473:pathology; D012957:Societies, Pharmaceutical; D013270:Stomach / Q000187:drug effects* / Q000473:pathology
chemical_list: D002273:Carcinogens; D008769:Methylnitronitrosoguanidine
keywords: Colon; Glandular stomach; Liver; Micronucleus assay; N-methyl-N′-nitro-N-nitrosoguanidine (MNNG); Repeated dose study