Procarbazine-induced specific-locus mutations in male mice

Ehling, U.H.; Neuhäuser, A.

doi:10.1016/0027-5107(79)90163-5

Cited by 109 publications

(25 citation statements)

References 16 publications

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“…These frequency data are in accord with mutation frequencies determined indirectly through the specific locus test (10,11) and frequency data obtained for sperm or testes from lacI and lacZ transgenic mice (1,12). The only other instance where a decline in mutation frequency has been observed within a lineage was reported by Witkin (13).…”

Section: Discussionsupporting

confidence: 82%

Mutation frequency declines during spermatogenesis in young mice but increases in old mice

Walter

Intano

McCarrey

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

125

121

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Five percent of live-born human offspring will have a genetic disorder. Of these, 20% are because of germ-line de novo mutations. Several genetic diseases, such as neurofibromatosis and Duchenne muscular dystrophy, are associated with a high percentage of de novo germ-line mutations. Until recently, a direct analysis of spontaneous mutation frequencies in mammalian germ cells has been prevented by technical limitations. We have measured spontaneous mutation frequencies in a lacI transgene by using enriched populations of specific spermatogenic cell types. Similar to previously published results, we observed a lower mutation frequency for seminiferous tubule cell preparations, which contain all stages of spermatogenesis, relative to somatic tissues. We made the unexpected observation of a decline in mutation frequency during spermatogenesis, such that the mutation frequencies of type B spermatogonia and all subsequent stages of spermatogenesis are lower than the frequency for primitive type A spermatogonia. In addition, spermatogenic cells from old mice have significantly increased mutation frequencies compared with spermatogenic cells from young or middle-aged mice. Finally, the mutation frequency was observed to increase during spermiogenesis in postreplicative cell types when spermatogenic cells were obtained from old mice.From a genetic perspective, germ cells are profoundly different from somatic cells because they carry the genetic information that will direct the development of the next generation, not simply the next daughter cell. Thus, safeguarding the integrity of germ-line DNA might provide evolutionary advantages. Indeed, in mice, mutation frequencies obtained from mixed populations of germ cells are lower than for somatic tissues (1). This was demonstrated by using a transgenic system in which the bacteriophage genome carrying the lacI repressor gene and the ␣lacZ gene from the prokaryotic lac operon was introduced into the mouse genome as a transgene. DNA was recovered from genomic DNA preparations by packaging and used to infect a strain of Escherichia coli carrying a lacZ (␤-galactosidase) gene, but lacking a functional lacI gene. Mutation of the lacI gene renders a blue plaque on agarose containing the chromogenic substrate 5-bromo-4-chloro-3-indolyl-␤-D-galactopyranoside (X-gal). In contrast, other studies using a lacI transgenic mouse (2) or a lacZ transgenic mouse (3) did not report a significant difference in mutation frequencies for spermatogenic cells compared with somatic cells.Although provocative, interpretation of the results demonstrating a lower mutation frequency for male germ cells is complicated by the fact that adult seminiferous tubules contain a mixture of spermatogenic cell types encompassing all stages of spermatogenesis. Spermatogonia serve as the stem cells for spermatogenesis and undergo mitotic divisions that give rise to cells that will either retain their identity as spermatogonia to maintain the stem cell population or enter meiosis to become primary spermatocy...

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Section: Discussionsupporting

confidence: 82%

Mutation frequency declines during spermatogenesis in young mice but increases in old mice

Walter

Intano

McCarrey

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

125

121

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“…Results along these lines have already been obtained by Ehling and coworkers on mitomycin C and procarbazine (5,6), but progress is slow, compared to that possible with radiation studies, owing to the lower rautagenicity oE these compounds relative to that from X rays. In contrast, the high mutagenicity of ENU offers an excellent opportunity for an in-depth study of this compound.…”

Section: Chemicalsmentioning

confidence: 77%

“…In comparison with other • chemicals that have shown a positive mutagenic effect in the mouse, ENU may be classed as a supermutagen. Thus, the highest reported mutation frequency obtained from a single dose of any other chemical is 16 mutations in 45,413 offspring produced by an injected dose of 600 mg/kg of procarbazine (6) . In our laboratory, the current mutation frequency from ENU at 250 mg/kg is 160 mutations in 29,577 offspring.…”

Section: Chemicalsmentioning

confidence: 98%

Problems and Solutions in the Estimation of Genetic Risks from Radiation and Chemicals

Russell

1981

Measurement of Risks

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Extensive investigations with mice on the effects of various physical and biological factors, such as dose rate, sex and cell stage, on radiation-induced mutation have provided an evaluation of the genetics hazards of radiation in man. The mutational results obtained in both sexes with progressive lowering of the radiation dose rate have permitted estimation of the mutation frequency expected under the low-level radiation conditions of most human exposure. Supplementing the studies on mutation frequency are investigations on the phenotypic effects of mutations in mice, particularly anatomical disorders of the skeleton, which allow an estimatio.. of the degree of human handicap associated with the occurrence o£ parallel defects in man. -Estimation of the genetic risk from chemical mutagens is much more difficult, and the research is much less advanced. Results on transmitted mutations in mice indicate a poor correlation with mutation induction in non-mammalian organisms. On the one hand, mice show little or no mutagenic response to several compounds that are highly mutagenic in other systems. On the other hand, recent results with ethylnitrosourea show that a single injection of 6 mg per mouse of this compound induces a mutation rate 75,000 times greater than that considered as a maximum permissible level of risk from a whole year of exposure to radiation. Further investigation in mice is obviously needed, not rcial orodu T necessarily c

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“…Chemicals which are known to induce specific locus mutations on spermatogonia in the mouse specific locus test include triethylenemelamine (Cattanach 1966), mitomycin C (Ehling 1974), procarbazine (Ehling and Neuhauser 1979) and ENU (Russell et al 1979) . The induced mutation frequency of ENU was higher than that of the other chemical mutagens.…”

Section: Resultsmentioning

confidence: 99%

“…The induced mutation frequency of ENU was higher than that of the other chemical mutagens. The frequencies of homozygous viable mutations induced by mitomycin C (Ehling 1980) and procarbazine (Ehling and Neuhauser 1979) were reported to be 75% and 76%, respectively. The origin of mutations induced by these chemicals might have been mainly base-pair changes.…”

Section: Resultsmentioning

confidence: 99%

Genetic analysis of mutants in mice induced by N-ethyl-N-nitrosourea.

Murota

Shibuya

1983

The Japanese journal of genetics

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Specific locus tests of the effects of N-ethyl-N-nitrosourea (ENU) on mouse spermatogonia using visible loci and hemoglobin beta-chain (Hbb) locus have been performed.Male wild-type (C3Hf/He) mice were injected intraperitoneally with ENU. Eight weeks after injection, the males were mated with tester strain females (PW) homozygous for six visible recessive genes. Ten visible and 2 hemoglobin mutants were obtained.The mutation frequency was 60.3 x 10-5/locus/generation. These mutations were all heritable, and nine out of ten mutations were viable under homozygous conditions. The results suggest that the mutations induced by ENU on spermatogonia of mice might have resulted from events at the genic rather than the chromosomal level.

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Procarbazine-induced specific-locus mutations in male mice

Cited by 109 publications

References 16 publications

Mutation frequency declines during spermatogenesis in young mice but increases in old mice

Mutation frequency declines during spermatogenesis in young mice but increases in old mice

Problems and Solutions in the Estimation of Genetic Risks from Radiation and Chemicals

Genetic analysis of mutants in mice induced by N-ethyl-N-nitrosourea.

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