Specific Locus Mutation in Mice

Ehling, U.H. (1977) Dominant lethal mutations in male mice. Arch. Toxicol., 38, 1-11 Ehling, U.H. (1978) Specific-locus mutations in mice. In Hollaender, A. de Serres, F.J., eds,... 

Ehling, U.H. Specific-locus mutations in mice, pp. 233-256. In A. Hollaender and F.J. de Serres, Eds. Chemical Mutagens Principles and Methods for Their Detection. Vol. 5. New York Plenum Press, 1978. 

Ehling, U.H., J. Favor, J. Kratochvilova, and A. Neuhauser-Klaus. Dominant cataract mutations and specific-locus mutations in mice induced by radiation or ethylnitrosourea. Mutat. Res. 92 181-192, 1982. 

Ethylene oxide was ineffective in inducing morphological-specific locus mutations in spermatogonial stem cells however, it produced dominant visible and electro-phoresis-specific locus mutants in male mice, assumed to be derived from poststem cells. 

The two purple adenine genes, ad-3A and ad-3B, are closely linked. By using a forced heterokaryon heterozygous for the ad-3 A and the ad-3B locus, Webber and de Serres were able to show that X-ray-induced specific-locus mutations in the ad-3 region were either point mutations or chromosome deletions (Webber and de Serres, 1965). The same classes of mutations are picked up in the specific-locus system in mice (Russell, 1951,1967). To sunmiarize in de Serres purple adenine system we have a eukaryotic, microbial assay system in which the same type of mutations can be isolated as in mammals. However, because it is a microbial system, it is considerably easier to perform quantitative mutagenesis studies with this system than with mice. 

U. H. Ehling and A. Neuhauser, Procarbazine-induced specific locus mutation in male mice, Mutat. Res. 59, 245-256 (1979). 

It is most important—but outside the scope of this article—that such comparisons of spontaneous and induced mutation rates both in vitro and in vivo (e.g., Russell s, 1951, specific-locus system in mice) be extended. In this manner, one of the chasms separating in vitro mutagen assays and mutagenic effects in man (namely, the differences between the mutagen response of mammalian somatic cells in vitro and that of the whole mammal) can be bridged. 

Selby, P.B. and Olson, W.H. (1981). Methods and criteria for deciding whether specific-locus mutation-rate data in mice indicates a positive, negative or inconclusive result. Mutation Res. 83 403-418. 

The gene mutation test systems in mice include the specific locus test, in which wild-type treated males are crossed with females carrying recessive mutations for visible phenotypic effects. The F progeny have the same phenotype as the wild-type parent unless a mutation, corresponding to a recessive mutant marker, has occurred. Such tests... 

Mailing, H.V., and L.R. Valcovic. A biochemical specific locus mutation system in mice. Arch. 

Ehling, U.H. Neuhauser-Klaus, A. (1988) Induction of specific-locus and dominant-lethal mutations in male mice by diethyl sulfate (DES). Mutat. Res., 199, 191-198... 

A recently developed version of the specific-locus test detects electrophoretic protein variants at at least 21 loci.101 198 It is based on early test-system development by Mailing and Valcovic270 and Soares.1+24 A significant increase in the mutation frequency for ENU has been demonstrated with this test. 95 Two inbred strains of mice are used that differ at 10 loci whose protein products are electrophoretically demonstrable. In addition, mutations resulting in the loss of any of 11 other proteins common to the two strains can be detected. Males of either strain are exposed to the test substance, and, at the desired time after exposure, they are mated with females of the other strain. Later, all parental and Fi animals are examined for the biochemical characters of interest. 

The specific-locus test is not intended for human risk estimation. The seven loci sampled may not be representative of the whole genome. To continue the example of the appendix to this chapter, a mutation rate of 0.000003 per seven loci corresponds to 0.009 for 20,000 loci, if this is taken as the haploid gene number. This is nearly 1% per zygote, not a negligible number. It would be desirable to have methods to measure mutations in the entire genome, or in an entire chromosome, such as are used in Drosophila. Such methods are being developed in mice, but cure not yet suitable for routine use. 

Another, and the main, purpose of mutagenicity testing is to detect the potentiality of environmental chemicals to produce mutations in germ cells that will be transmitted to the descendant generations. Drosophila can be used most conveniently for this purpose. Testing with mice provides very useful information for extrapolation to man, but it requires large-scale experiments, especially when the specific locus method is used. In contrast, this method can be used... 

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