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Induction of specific-locus and dominant-lethal mutations in male mice by diethyl sulfate (DES)
U H Ehling1, A Neuhäuser-Klaus
1Institut für Säugetiergenetik, Gesellschaft für Strahlen- und Umweltforschung, Neuherberg, F.R.G.
Abstract:
Diethyl sulfate (DES), a monofunctional alkylating agent, induces mutations and chromosomal aberrations in many different organisms and cell systems, including dominant-lethal mutations in male mice. However, until now it could not be demonstrated that DES induces specific-locus mutations in mice. This observation would contradict the close correlation observed between the induction of dominant-lethal mutations and specific-locus mutations in mice with other chemicals. DES induces dominant-lethal and specific-locus mutations in spermatozoa and late spermatids of mice. The mutation frequency for dominant-lethal mutations is dose-dependent, while for specific-locus mutations it is independent of the dose. In the mating interval 5-8 days post-treatment the mutation frequency for 200 mg/kg DES is 17.0 X 10(-5) and for 300 mg/kg 7.5 X 10(-5) mutations per locus. The dose-dependent increase of dominant-lethal mutations probably reduced the chance of recovering specific-locus mutations. The importance of these findings for mutagenicity testing is discussed.
Insights
Diethyl sulfate (DES) induces specific-locus mutations in mouse sperm, contradicting previous findings. The study suggests dominant-lethal mutations may mask specific-locus mutation recovery.
Area of Science:
- Toxicology
- Genetics
- Mutagenesis
Background:
- Diethyl sulfate (DES) is a monofunctional alkylating agent known to induce mutations and chromosomal aberrations.
- Previous studies indicated DES causes dominant-lethal mutations in male mice but not specific-locus mutations.
- This lack of specific-locus mutation data contradicted the established correlation with dominant-lethal mutations for other chemicals.
Purpose of the Study:
- To investigate whether diethyl sulfate (DES) induces specific-locus mutations in mice.
- To reconcile the discrepancy between DES's known mutagenicity and the absence of specific-locus mutation data.
- To evaluate the impact of dominant-lethal mutations on the recovery of specific-locus mutations.
Main Methods:
- Mice were treated with varying doses of diethyl sulfate (DES).
- Dominant-lethal mutations and specific-locus mutations were assessed in male mice at different post-treatment intervals.
- Mutation frequencies were analyzed in relation to DES dosage and cell stage.
Main Results:
- Diethyl sulfate (DES) was demonstrated to induce both dominant-lethal and specific-locus mutations in mouse spermatozoa and late spermatids.
- Dominant-lethal mutation frequency showed a dose-dependent relationship with DES exposure.
- Specific-locus mutation frequency was independent of DES dose, with observed frequencies of 17.0 x 10^-5 (200 mg/kg) and 7.5 x 10^-5 (300 mg/kg) per locus.
Conclusions:
- Diethyl sulfate (DES) is confirmed as a mutagen capable of inducing specific-locus mutations in mice.
- The dose-dependent increase in dominant-lethal mutations likely interfered with the detection and recovery of specific-locus mutations.
- These findings have significant implications for the interpretation of mutagenicity testing protocols and chemical risk assessment.