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Alkylated Imino Sugars, Reversible Male Infertility-Inducing Agents, Do Not Affect the Genetic Integrity of Male Mouse Germ Cells During Short-Term Treatment Despite Induction of Sperm Deformities¹

Institute for Biogenesis Research,³ University of Hawaii School of Medicine, Honolulu, Hawaii 96822 Department of Obstetrics and Gynecology,⁴ Fukushima Medical University, Fukushima, 960-1295, Japan The Glycobiology Institute,⁵ Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom

Reversible infertility can be induced in male mice by oral administration of the alkylated imino sugars N-butyldeoxynojirimycin (NB-DNJ) and N-butyldeoxygalactonojirimycin (NB-DGJ). Spermatozoa of these mice have grossly misshapen heads and reduced motility. Because NB-DNJ and related compounds may hold promise as nonhormonal male contraceptives, a comprehensive examination of their effects on male reproduction is necessary. To this end, we further examined reproductive properties of the dysmorphic spermatozoa that are produced after short-term imino sugar administration at the minimal dose that completely abolishes the ability of male C57BL/6 mice to produce offspring by natural mating. Here, we report that, in vitro, the abnormal spermatozoa from the NB-DNJ- and NB-DGJ-treated mice were unable to fertilize oocytes. In addition, we investigated whether the imino sugars damage the genetic integrity of spermatozoa. To test this, we microsurgically injected deformed spermatozoa from imino sugar-treated males into oocytes. The deformed spermatozoa from the testis were able to activate oocytes very efficiently, but those from the cauda epididymis often failed to do so. This problem was overcome when the sperm-injected oocytes were treated with a parthenogenetic agent, Sr²⁺. Oocytes injected with the misshapen spermatozoa from NB-DNJ- and NB-DGJ-treated mice developed (with or without Sr²⁺ treatment) into live offspring that grew normally and were normally fertile. This indicates that during short-term administration, alkylated imino sugars alter sperm morphology and physiology but do not diminish the genetic potential of spermatozoa.

¹ Supported by the Harold Castle Foundation, the Kosasa Family Foundation, the Victoria Geist Foundation (R.S. and R.Y.), Oxford GlycoSciences/ Celltech UK (C.M.W), and NIH Grant 1 U01 HD45861 (F.M.P. and A.C.S.)

² Correspondence: Aarnoud C. van der Spoel, The Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K. FAX: 44 01865 27 5216; aarnoud.vanderspoel{at}bioch.ox.ac.uk

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