N-butyldeoxygalactonojirimycin induces reversible infertility in male CD rats

Vijayalaxmi Gupta, Sheri A. Hild, Sudhakar R Jakkaraj, Erick J Carlson, Henry L Wong, C Leigh Allen, Gunda Georg, Joseph S. Tash

Research output: Contribution to journalArticlepeer-review

Abstract

This study shows for the first time that an iminosugar exerts anti-spermiogenic effect, inducing reversible infertility in a species that is not related to C57BL/6 male mice. In CD rats, Nbutyldeoxygalactonojirimycin (NB-DGJ) caused reversible infertility at 150 mg/kg/day when administered daily as single oral dose. NB-DGJ inhibited CD rat-derived testicular β-glucosidase 2 (GBA2) activity at 10 µM but did not inhibit CD rat-derived testicular ceramide-specific glucosyltransferase (CGT) at doses up to 1000 µM. Pharmacokinetic studies revealed that sufficient plasma levels of NB-DGJ (50 µM) were achieved to inhibit the enzyme. Fertility was blocked after 35 days of treatment and reversed one week after termination of treatment. The rapid return of fertility indicates that the major effect of NB-DGJ may be epididymal rather than testicular. Collectively, our in vitro and in vivo studies in rats suggest that iminosugars should continue to be pursued as potential lead compounds for development of oral, non-hormonal male contraceptives. The study also adds evidence that GBA2, and not CGT, is the major target for the contraceptive effect of iminosugars.

Original languageEnglish (US)
Article number301
JournalInternational Journal of Molecular Sciences
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2020

Bibliographical note

Funding Information:
This work was supported by the Contraception Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development through contracts HHSN275200503400C and HHSN275201300017C (to GIG and JT). The rat mating trial was supported by the National Institute of Child Health and Human Development contract N01-HD-2-3338 awarded to BIOQUAL, Inc.

Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Contraceptive
  • Iminosugar
  • NB-DGJ
  • NB-DNJ

PubMed: MeSH publication types

  • Journal Article

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