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Transgenic Rodent Assay for Quantifying Male Germ Cell Mutant Frequency
Published on: August 6, 2014
A time-course characterization of male reproductive toxicity in rats treated with methyl methanesulphonate (MMS)
Kazuya Kuriyama1, Ryohei Yokoi, Kazuo Kobayashi
1Toxicology research laboratories, Kissei Pharmaceutical Co., Ltd., Minamiazumi, Nagano, Japan.
Abstract:
Methyl methanesulphonate (MMS), a potent alkylating agent and testicular toxicant, was orally administered to rats for 5 days at doses of 20, 30, and 40 mg/kg. During the recovery period of 5 weeks, males were evaluated for multiple endpoints such as organ weights, fertility, and sperm parameters. The 5-week recovery periods are designated as follows: Day 1 (1 day after final treatment); Week 1, Week 2, Week 3, Week 4, and Week 5 (first, second, third, fourth, and fifth week after final treatment). A clear time-course of dominant lethals was observed. The peak severities of the dominant lethals were observed in Week 2. It was judged that the most sensitive cellular targets for the dominant lethals are late spermatids. Sperm examination revealed a clear time-course and dose-dependent changes in the frequency of sperm morphological abnormalities. The peak severities of the sperm morphological alterations in cauda epididymis were observed in Week 4. Sensitive cellular stages for the induction of sperm morphological abnormalities were judged to be late spermatocytes and early spermatids. The most frequently observed type of morphologically abnormal spermatozoa was tailless sperm, followed by no-hook head sperm. Although the initial cause for both sperm morphological alterations and dominant lethals was suggested to be genetic insult to the germ cells, there were no obvious relationships observed between these two findings.
Insights
Methyl methanesulphonate (MMS) causes testicular toxicity and dominant lethal mutations in male rats. Peak effects on dominant lethals occurred at week 2, and sperm abnormalities peaked at week 4.
Area of Science:
- Reproductive toxicology
- Genetics
- Environmental health
Background:
- Methyl methanesulphonate (MMS) is a known alkylating agent and testicular toxicant.
- Understanding the long-term effects of MMS exposure on male reproductive health is crucial.
Purpose of the Study:
- To investigate the time-course and dose-dependency of reproductive toxicity induced by oral MMS administration in male rats.
- To identify sensitive cellular targets for dominant lethals and sperm morphological abnormalities.
Main Methods:
- Male rats were orally administered MMS at doses of 20, 30, and 40 mg/kg for 5 days.
- Reproductive endpoints, including organ weights, fertility, sperm parameters, and dominant lethality, were assessed over a 5-week recovery period.
- Sperm morphology was analyzed, and sensitive germ cell stages were identified.
Main Results:
- A clear time-course and dose-dependent induction of dominant lethals were observed, with peak severity at Week 2, primarily affecting late spermatids.
- Sperm morphological abnormalities, including tailless and no-hook head sperm, showed a time-course and dose-dependent pattern, peaking at Week 4.
- Sensitive cellular stages for sperm abnormalities were late spermatocytes and early spermatids.
Conclusions:
- MMS induces significant reproductive toxicity in male rats, affecting both germ cell integrity and fertility.
- While both dominant lethals and sperm abnormalities stem from genetic insults, their peak effects and sensitive stages differ, with no direct correlation observed between the two endpoints.
