Acrylamide (AA), known to induce dominant lethals in male rodents, was studied in the mouse heritable translocation test by using intraperitoneal injections on 5 consecutive days. Matings on days 7-10 following the last injection yielded a high frequency of translocation carriers in the F1 male population, which demonstrated that acrylamide is an effective inducer of translocations in postmeiotic germ cells. As an inducer of both dominant lethals and heritable translocations in late spermatids and early spermatozoa, AA is similar to alkylating agents such as ethylmethanesulfonate and ethylene oxide. However, AA's chemical structure, the nature of adducts formed with DNA, and it lack of mutagenicity in bacteria suggest a different mechanism as the basis for AA's germ cell mutagenicity.

Male mice were subjected to repeated inhalation exposures to different concentrations (165, 204, 250, or 300 ppm) of ethylene oxide (EtO) during an 8.5-week period. Transmitted clastogenic effects of these exposures were measured in terms of induction of dominant lethal mutations and heritable translocations. The concentration-response curves for both endpoints are not linear but are markedly concave upward. Significant increases in dominant lethals were detected at all concentrations, except the lowest one. In comparison, the incidences of heritable translocations were significantly increased at all concentrations.

As measured by' specific-locus mutations in mouse spermatogonia, fractionating a dose of 100 mg of ethylnitrosourea per kg of body weight into doses of 10 mg/kg injected intraperitoneally at weekly intervals greatly reduces the mutation frequency compared with that from a single dose of 100 mg/kg. Because there is independent evidence that the doses of 10 and 100 mg/kg reach the germ cells in amounts directly proportional to the injected dose, the lower mutational response with the fractionated dose is attributed to repair. The induced mutation rate expected from a single 10-mg/kg dose (on the assumption that this would be 1/10th the rate observed after 10 such doses) would be only 75% ofthe spontaneous mutation rate. Mouse spermatogonia apparently have an efficient repair system that is effective even against a potent mutagen.A companion paper (1) reports the results obtained from two series of experiments exploring the shape of the dose-response curve for specific-locus mutations induced in mouse spermatogonia by N-ethyl-N-nitrosourea (ENU). The second series involved doses of 25, 50, 75, and 100 mg/kg. When the animals in these experiments had been producing offspring for approximately one year, it appeared (and has since been confirmed with the completion of the experiments) that the mutation frequencies at the lower doses would fall below a linear interpolation between the control and 100-mg/kg frequencies. It was clearly desirable to find out what would happen at still lower doses. However, the mutation frequencies at 25 and 50 mg/ kg were already so low that it was probable that single-dose experiments below 25 mg/kg would require prohibitively large numbers of offspring to determine reliable mutation rates. To avoid this difficulty, an experiment with a fractionated dose was started. Doses of 10 mg/kg were injected at weekly intervals for a total dose of 100 mg/kg, the rationale being that doses spaced a week apart would be solely additive and, therefore, that 1/10th of the mutation frequency obtained with this exposure might approximate what would be expected from a single 10-mg/kg dose. This experiment is still proceeding, but the results obtained to date are informative, and a progress report is therefore presented here. A brief account of an earlier stage in the experiment was presented in a symposium paper (2). MATERIALS AND METHODSENU, synthesized in our laboratory by D. G. Doherty, was dissolved in phosphate buffer (3) adjusted to pH 6. The dose injected intraperitoneally was matched to the body weight of the animal by adjusting the volume of solution injected, which approximated 1 ml. Wild-type (101 x C3H)F1 male mice were injected with a dose of10 mg/kg. One week later, they received another dose of 10 mg/kg, and this was repeated at weekly intervals for a total dose of 100 mg/kg. The animals were 5 weeks old at the time of the first injection and, therefore, =14 weeks old when the last injection was given. All injections were completed within 1 hr .after dissolving the chemical. Seven ...

A semisterile male translocation heterozygote [t(2; 14) 1Gso] that exhibited neurological symptoms and an inability to swim (diver) was found among the offspring of male mice treated with triethylenemelamine. All breeding and cytogenetic data showed a complete concordance between translocation heterozygosity and the neurological disorders. Homozygosity for the translocation seemed to be lethal at an early embryonic stage. Despite the distinctive neurologic symptoms, no anatomic or histological defects in either the ear or in the central nervous system were observed. Thus, a balanced chromosomal translocation can produce disease with an inheritance pattern that mimics a single dominant gene defect.

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