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Studies on mutations at the lacZ locus obtained after treatment of male postmeiotic stage in Muta™ mouse with iPMS
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42 Kato, T., K. Matsumoto and T. Ohta, Institute of Environmental Toxicology, Kodaira, Tokyo 187 (Japan) The size of micronuclei in mouse bone marrow cells induced by rotenone
Induction of micronuclei by rotenone was investigated in mouse bone marrow cells. Rotenone, an inhibitor of spindle microtubule assembly, has been reported to induce aneuploidy, polyploidy, and endoreduplication, but not structural chromosome aberrations in cultured Chinese hamster cells. CD-1 male mice were administered rotenone at 15 mg/kg by intraperitoneal injection 48 h before sampling. Weak but significant increases in the frequency of micronucleated polychromatic erythrocytes (0.59%) over the control (0.22%) were detected. Most of the induced micronuclei (95.5%) were normal-sized single (93.2%) and double (2.3%) ones. in contrast, 26.0% of the micronuclei induced by ¢olchicine, which is known to induce both structural and numerical chromosome aberrations in cultured mammalian cells, were large-sized ones including ring type (4.9%) and crescent type (4.4%). Rotenone seems to have a different action from other spindle poisons like colchicine and vincristine in the process of micronucleus formation, 43 Katoh, M. t, T. Inomata 2, F. Suzuki t, N. Ishihara t M. Kusanagi 3, T. Shibuya t K. lntehar 4 and B. Myhr 4, t Food and Drug Safety Center, 729.50chiai, Hadano, Kanagawa 257, 2 Azabu University, 1-17-71 Fuchinobe, Sagamihara, Kanagawa 229, ~ Japan Laboratory Animals Inc., 6-10-40 Kasuga-cho, Nerima-ku, Tokyo 179 (Japan) and 4 Hazleton Washington, Vienna, VA 22182 (USA) Studies on mutations at the lacZ locus obtained after treatment of male postmeiotic stage in MutaTMMOusewith IPMS
Isopropyl methanesuifonate (iPMS) induces a high frequency of dominant lethal mutations in
postmeiotic male germ cells of mice. However, iPMS was shown to not induce a high frequency of chromosome aberrations at the first cleavage metaphase. MutaXMMouse (MM) is a transgenic mouse designed to detect chemically induced mutational events in vivo by isolating the genomic DNA, packaging the integrated lacZ genes into lambda preheads, and analyzing bacterial plaques. Accordingly, the present study using MM was undertaken to clarify whether gene mutations are responsible for the high incidence of iPMS-induced dominant lethal mutations in the postmeiotic stage. Male MM animals were given single intraperitoneal injections of 200 mg/kg iPMS. Four males were killed at 3 and 12 days after treatment. Sperm DNA was extracted from vasa deferentia and caudal epididymus. The iPMS-induced mutant frequency was not so high as to readily explain the high incidence of dominant lethal mutations. This result suggests that the high frequency of dominant lethal mutations induced by iPMS is not due to gene mutations as detectable by this assay system.
44 Kawanishi, S., and K. Yamamoto, Department of Public Health, Faculty of Medicine, Kyoto University, Kyoto 606 (Japan) Radical formation and DNA damage induced by hydrazine derivatives in the presence of metal ions
Most hydrazine derivatives have been shown to be carcinogenic. These hydrazines induce mutation in bacteria without addition of S9 mix. Therefore, it is considered that hydrazines exert their toxic action through a mechanism other than drug-metabolizing enzyme system. In this study, DNA damage induced by hydrazine derivatives in the presence of metal ions was investigated by a DNA sequencing technique using a2p. DNA. In the presence of Mn(ll) or Mn(lll), hydtazine caused DNA cleavage at every nucleotide without marked site specificity. ESR-spin trapping experiments showed that hydroxyl free radical ('OH) is generated during the Mn-cata-
42 Kato, T., K. Matsumoto and T. Ohta, Institute of Environmental Toxicology, Kodaira, Tokyo 187 (Japan) The size of micronuclei in mouse bone marrow cells induced by rotenone
Induction of micronuclei by rotenone was investigated in mouse bone marrow cells. Rotenone, an inhibitor of spindle microtubule assembly, has been reported to induce aneuploidy, polyploidy, and endoreduplication, but not structural chromosome aberrations in cultured Chinese hamster cells. CD-1 male mice were administered rotenone at 15 mg/kg by intraperitoneal injection 48 h before sampling. Weak but significant increases in the frequency of micronucleated polychromatic erythrocytes (0.59%) over the control (0.22%) were detected. Most of the induced micronuclei (95.5%) were normal-sized single (93.2%) and double (2.3%) ones. in contrast, 26.0% of the micronuclei induced by ¢olchicine, which is known to induce both structural and numerical chromosome aberrations in cultured mammalian cells, were large-sized ones including ring type (4.9%) and crescent type (4.4%). Rotenone seems to have a different action from other spindle poisons like colchicine and vincristine in the process of micronucleus formation, 43 Katoh, M. t, T. Inomata 2, F. Suzuki t, N. Ishihara t M. Kusanagi 3, T. Shibuya t K. lntehar 4 and B. Myhr 4, t Food and Drug Safety Center, 729.50chiai, Hadano, Kanagawa 257, 2 Azabu University, 1-17-71 Fuchinobe, Sagamihara, Kanagawa 229, ~ Japan Laboratory Animals Inc., 6-10-40 Kasuga-cho, Nerima-ku, Tokyo 179 (Japan) and 4 Hazleton Washington, Vienna, VA 22182 (USA) Studies on mutations at the lacZ locus obtained after treatment of male postmeiotic stage in MutaTMMOusewith IPMS
Isopropyl methanesuifonate (iPMS) induces a high frequency of dominant lethal mutations in
postmeiotic male germ cells of mice. However, iPMS was shown to not induce a high frequency of chromosome aberrations at the first cleavage metaphase. MutaXMMouse (MM) is a transgenic mouse designed to detect chemically induced mutational events in vivo by isolating the genomic DNA, packaging the integrated lacZ genes into lambda preheads, and analyzing bacterial plaques. Accordingly, the present study using MM was undertaken to clarify whether gene mutations are responsible for the high incidence of iPMS-induced dominant lethal mutations in the postmeiotic stage. Male MM animals were given single intraperitoneal injections of 200 mg/kg iPMS. Four males were killed at 3 and 12 days after treatment. Sperm DNA was extracted from vasa deferentia and caudal epididymus. The iPMS-induced mutant frequency was not so high as to readily explain the high incidence of dominant lethal mutations. This result suggests that the high frequency of dominant lethal mutations induced by iPMS is not due to gene mutations as detectable by this assay system.
44 Kawanishi, S., and K. Yamamoto, Department of Public Health, Faculty of Medicine, Kyoto University, Kyoto 606 (Japan) Radical formation and DNA damage induced by hydrazine derivatives in the presence of metal ions
Most hydrazine derivatives have been shown to be carcinogenic. These hydrazines induce mutation in bacteria without addition of S9 mix. Therefore, it is considered that hydrazines exert their toxic action through a mechanism other than drug-metabolizing enzyme system. In this study, DNA damage induced by hydrazine derivatives in the presence of metal ions was investigated by a DNA sequencing technique using a2p. DNA. In the presence of Mn(ll) or Mn(lll), hydtazine caused DNA cleavage at every nucleotide without marked site specificity. ESR-spin trapping experiments showed that hydroxyl free radical ('OH) is generated during the Mn-cata-