Reversible infertility in male mice after oral administration of alkylated imino sugars: a nonhormonal approach to male contraception.

Abstract

During mammalian spermatogenesis, male germ cells undergo a dramatic transformation, which includes a change of shape, nuclear condensation, and development of specialised structures, such as an acrosome, and a flagellum with a mitochondrial sheath. We have found a previously undescribed pharmacological approach to intervene in these events. After oral administration of the alkylated imino sugar N-butyldeoxynojirimycin (NB-DNJ) to mice, epididymal spermatozoa displayed a spectrum of abnormal head shapes, and acrosomal antigens were mostly absent or displayed irregular patterns. In addition, the mitochondria of these cells often had an aberrant morphology, and were arranged in relatively short and wide mitochondrial sheaths. The motility of the affected spermatozoa was severely impaired. After 3 weeks of administration of NB-DNJ, male mice became sterile, and regained their fertility during the fourth week off drug. The NB-DNJ-induced infertility was not associated with a reduction in the serum testosterone level. Biochemically, the capacity of imino sugars to impair spermatogenesis was associated with their potential to attenuate the biosynthesis of glucosylceramide-based sphingolipids. Our study reveals that male fertility is affected by partial glycosphingolipid depletion, or, alternatively, by a distinct as yet unidentified property that is shared by alkylated imino sugars that inhibit glucosylceramide biosynthesis. These compounds therefore may be new leads in the development of a male contraceptive, especially because NB-DNJ has already been through extensive evaluation in various mammals, including man.

• Authors: Aarnoud C van der Spoel, Mylvaganam Jeyakumar, Terry D Butters, Harry M Charlton, Harry D Moore, Raymond A Dwek, Frances M Platt
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 99 Issue 26 Pg. 17173-8 (Dec 24 2002) ISSN: 0027-8424 [Print] United States
• PMID: 12477936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Contraceptive Agents, Male
• 1-Deoxynojirimycin
• Testosterone
• miglustat

Topics

• 1-Deoxynojirimycin (analogs & derivatives, pharmacology)
• Administration, Oral
• Animals
• Contraceptive Agents, Male (pharmacology)
• Dose-Response Relationship, Drug
• Female
• Fertility (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Organ Size (drug effects)
• Sperm Count
• Testis (drug effects, pathology)
• Testosterone (blood)