This study was conducted to assess whether a 2-week treatment period is as effective as 4-week treatment for detection of drug-induced toxicity on the male rat reproductive organs using methyl methanesulfonate (MMS). A two-week study at dose levels of 20 or 40 mg/kg and a 4-week study with 20 mg/kg were conducted. The results can be summarized as follows. No deaths and no apparent clinical signs were observed. Body weights and food consumption were decreased at 40 mg/kg in the 2-week study along with testis and epididymis weights. In the 4-week study, epididymis weights were decreased at 20 mg/kg. The rats treated with 20 mg/kg in the 4-week study and those treated with 40 mg/kg in the 2-week study showed decrease of germ cells, exfoliation of germ cells, vacuolar degeneration of Sertoli cell and cell debris in epididymal ducts on histopathological observation. MMS impairment of spermatogenesis was confirmed by stage analysis. It was concluded that a treatment period of 2 weeks is sufficient to allow evaluation of toxic effects of MMS on the male reproductive organs.

Abstract. Methyl methanesulphonate (MMS), a potent alkylating agent and testicular toxicant, was orally administered to rats for 5 days at 40 mg/kg. During the recovery period of up to 5 weeks, males were evaluated for testicular toxicity and sperm morphology. The 5-week recovery period were designated as follows: Day 1 (the day after final treatment); Week 1, Week 2, Week 3, Week 4 and Week 5 (1, 2, 3, 4 and 5 weeks after final treatment). Morphologically abnormal sperm increased beginning in Week 3, peaked in Week 4 and declined slightly in Week 5. Histopathological examinations indicated retention of step 19 spermatids at stage IX from Day 1 through Week 3. Quantitative evaluation of spermatogenic cells indicated a decrease in the number of late pachytene spermatocytes and early spermatids on Day 1. TUNEL examination showed a significantly high frequency of apoptosis in the meiosis cells in Week 1. In the present study, genetic damage induced by treatment with MMS affected spermatogenesis and a wide variety of spermatogenic cells in the testis. Apoptosis in the course of meiosis seemed to be involved in the elimination process of genetically insulted germ cells, and this process seems to play an important role in eliminating and/or decreasing the germ cells with retention of spermatids and the potential to express morphologically abnormal spermatozoa.

-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.

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