Lethal Mutations in Mammals

The reduction of fertile spikelets ( sterility ) caused by chemical mutagens is primarily due to recessive lethal mutations. In other cases, particularly after a high LET (linear energy transfer) irradiation, translocation and other gross chromosomal aberrations occur cf. dominant lethal mutations in mammals) and play a lethal role (Ekberg, 1969). Induced sterility may therefore be used as a sensitive measure of mutagenic action. Sterility may, however, also be caused by unspecific damage to the seed or plant. 

Bentley KS, Sarrif AM, Cimino MC, Auletta AE. 1994. Assessing the risk of heritable gene mutation in mammals Drosophila sex-linked recessive lethal test and tests measuring DNA damage and repair in mammalian germ cells. Environ Mol Mutagen 23 3-11. 

Sex-linked recessive lethal mutations were not produced in Drosophila fed ethanol solution containing 50 ppm 1,2-diphenylhydrazine for 3 days (Yoon et al. 1985). No oral genotoxicity studies of 1,2-diphenylhydrazine in mammals were located. 

Knudsen I, Hansen EV, Meyer AO, Poulsen E (1977) A proposed method for the simultaneous detection of germ-cell mutations leading to foetal death (dominant lethality) and of malformations (male teratogenicity) in mammals. Mutat Res, 478 267-270. 

Diepoxybutane is a potent bifunctional alkylating agent which reacts with DNA in vitro and in vivo. As a result, it is mutagenic in virtually all test systems including effects in somatic and germ cells of mammals exposed in vivo. In vivo, it induced DNA adducts, dominant lethal mutations and gene mutations in mice chromosomal aberrations... 

If the previous tests do not suffice for a decision, further testing in mammals is indicated. If the purpose is to get mammalian germinal data on whether a substance produces mutations, the specific-locus test is suitable because of its low background rate and the extent to which the test has been performed. It should be recognized, however, that chemicals that yield inconclusive results in short-term tests are likely to yield negative or inconclusive results in mouse tests. The dominant-lethal test may be used if the expected effect is chromosomal. 

The dominant-lethal test is the most relevant test for mutation production in mammals that is available at present. It has been used with hundreds of compounds, and has given very important information. The results of the dominant-lethal test must be carefully interpreted since there is a variation of responses in regard to sex and strain. In a case where the host-mediated test gives positive results and the dominant-lethal test is negative, it is most important that the dominant-lethal test be tried with other strains of mice (if the mouse is used as the indicator organism). 

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