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Methyl methanesulphonate (MMS) as a resource conserving and reliable positive control agent for male rat and male
J Ashby1, P A Lefevre, B M Elliott
1Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Abstract:
A single i.p. injection of methyl methanesulphonate (MMS; 40 mg/kg) to male rats, followed by their sequential mating over 4-28 days post-dosing, was shown to induce dominant lethal (DL) effects in two strains of rats and in four separate experiments. Activity was evident between 4 days post-dosing (sampling treated spermatozoa) and 28 days post-dosing (sampling treated early spermatids). The highest incidences of resorptions were seen between days 15 and 21 post-dosing, being approximately 1 week later than the peak of activity in the mouse. The DL effects seen were strong and could be detected as early as 4-10 days post-dosing, at which time only small reductions in pregnancy rates and total implantation numbers were seen. Similar, but weaker, mutagenic effects have been reported by Ehling et al. for MMS in mouse DL assays. These data indicate, therefore, that MMS provides a convenient positive control agent for both male rat and male mouse dominant lethal assays, requiring only approximately five treated males, each mated to two females at around 14 days post-dosing.
Insights
Methyl methanesulphonate (MMS) induces significant dominant lethal effects in male rats, detectable from 4 days post-dosing. This finding supports MMS as a reliable positive control for mutagenicity testing in rodents.
Area of Science:
- Toxicology
- Genetics
- Reproductive Toxicology
Background:
- Dominant lethal (DL) assays are crucial for evaluating mutagenicity.
- Methyl methanesulphonate (MMS) is a known mutagen, but its efficacy in rat DL assays requires further characterization.
Purpose of the Study:
- To investigate the dominant lethal (DL) effects of methyl methanesulphonate (MMS) in male rats.
- To establish MMS as a positive control agent for dominant lethal assays in rats and mice.
Main Methods:
- Male rats received a single intraperitoneal injection of MMS (40 mg/kg).
- Treated males were sequentially mated with females over 4-28 days post-dosing.
- Incidences of resorptions, pregnancy rates, and total implantation numbers were analyzed.
Main Results:
- MMS induced significant dominant lethal effects in two rat strains across four experiments.
- Mutagenic activity was observed from 4 to 28 days post-dosing, with peak effects between days 15-21.
- Strong DL effects were detected early (4-10 days post-dosing), with minimal impact on pregnancy rates initially.
Conclusions:
- MMS is a potent inducer of dominant lethal effects in male rats.
- MMS serves as a convenient and effective positive control for both male rat and male mouse dominant lethal assays.
- The study highlights the utility of MMS for standardized mutagenicity testing in rodent models.