Induction of gene mutations in germ cells of the mouse.

Abstract

Methods available to study the induction of gene mutations in mammalian germ cells are described. Results of specific locus experiments with mice indicate the importance of this test for the validation of short term tests. Out of 5 compounds studied extensively in the Environmental Research Programme of the Commission of the European Communities 2 induced mutations in the Salmonella typhimurium test and in the specific locus test, while 2 others induced mutations only in mammals. In contrast to radiation, chemical mutagens can express mutations in certain gametogenic stages only. The different gametogenic sensitivity of mammalian germ cells to chemical mutagens gives a clue for the evaluation of mutagenicity data. In the linear part of the dose-effect-curve fractionation of a dose of 600 mg/kg procarbazine reduced the yield of specific locus mutations. In the descending part of the dose-effect-curve fractionation of a dose increased the rate of specific locus mutations above the single total dose. Experiments with procarbazine indicate that oocytes are less sensitive than spermatogonia for the induction of specific locus mutations. The genetic risk is defined as the increase in percent of the spontaneous mutation rate. The genetic risk can be calculated with high confidence on the basis of relatively few animals in the experimental group. The ratio between the therapeutic dose and the doubling dose gives the percentage increase of the spontaneous mutation frequency of a patient (individual risk). The ratio between the population dose and the doubling dose gives the percentage increase of the spontaneous mutation frequency of a population (population risk). The quantification of the genetic risk of the first generation is possible on the basis of dominant cataract mutations in mice. All extrapolations are based on the assumption that man and mice are equally sensitive to the induction of gene mutations.