Electrophoretic variants for the stomach isozyme (ADH-C2) and liver isozyme (ADH-A2) of alcohol dehydrogenase in strains of Mus musculus have been used in genetic analyses to demonstrate close linkage between the structural genes (Ahd-3 and Adh-1, respectively) encoding these enzymes. No recombinants were observed between these loci among 126 backcross animals, which places them less than 0.8 centimorgans apart. Previous studies have positioned Adh-3, and a temporal locus (ADh-3t), on chromosome 3 (Holmes, "79; Holmes et al., "80). Kinetic analyses on partially purified preparations of these isozymes have demonstrated widely divergent catalytic properties and inhibitor specificities. The liver isozyme exhibited Michaelis constants that were nearly 3 orders of magnitude lower than the stomach isozyme for various alcohol and aldehyde substrates. Moreover, aminopropyl pyrazole strongly inhibited ADH-A2 (Ki=1.2M), whereas ADH-C2 was insensitive to inhibition under the conditions used. It is proposed that Adh-1 and Adh-3 are products of a recent gene duplication event during mammalian evolution and that considerable divergence in the active sites of these enzymes and the "temporal" genes controlling loci expression in differentiated tissues has subsequently occurred.
The clastogenic potential of sodium fluoride was determined both in vitro (using cultured human lymphocytes) and in vivo (using the rat bone-marrow micronucleus test). The incidence of chromosome aberrations in human lymphocyte cultures exposed to 20 or 40 micrograms/ml sodium fluoride (3 and 9% respectively) was significantly increased compared with control cultures (0.5%). However, the incidence of micronucleated polychromatic erythrocytes in male AP rats dosed 1000 mg/kg NaF (the maximum tolerated dose over 24 h) or 500 mg/kg NaF was similar to that in the animals dosed distilled water (vehicle control). Thus, sodium fluoride is clastogenic in vitro but not in vivo.
The methods used for the detection of chemically induced chromosome damage in male germ cells are discussed. These tests have been divided into direct and indirect cytogenetic methods. The direct methods assess chromosome damage in the dosed animal but analysis is restricted to the dividing spermatogonia and spermatocytes. Using indirect methods, chromosome damage is assessed in the F1 progeny of the dosed male and analysis covers all germ cell stages. Both methods can provide evidence of germ cell exposure but the data obtained from the indirect tests are considered more relevant since a positive result clearly constitutes unequivocal evidence of transmitted damage. The analysis of one-cell embryos from matings involving dosed parents is considered to be the most useful indirect test system since both structural and numerical aberrations in male and female F1 offspring can be assessed. Although relevant to the assessment of mutagenic hazard, the technically demanding methods used in the germ cell techniques prevent their use for preliminary screening programmes.
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