Differential Sensitivity of Mouse Strains to an N-Alkylated Imino Sugar: Glycosphingolipid Metabolism and Acrosome Formation

Abstract

This review deals with the pharmacological properties of an alkylated monosaccharide mimetic, N-butyldeoxynojirimycin (NB-DNJ). This compound is of pharmacogenetic interest because one of its biological effects in mice – impairment of spermatogenesis, leading to male infertility – depends greatly on the genetic background of the animal. In susceptible mice, administration of NB-DNJ perturbs the formation of an organelle, the acrosome, in early post-meiotic male germ cells. In all recipient mice, irrespective of reproductive phenotype, NB-DNJ has a similar biochemical effect: inhibition of the glucosylceramidase β-glucosidase 2 and subsequent elevation of glucosylceramide, a glycosphingolipid. The questions that we now need to address are: how can glucosylceramide specifically affect early acrosome formation, and why is this contingent on genetic factors? Here we discuss relevant aspects of reproductive biology, the metabolism and cell biology of sphingolipids, and complex trait analysis; we also present a speculative model that takes our observations into account.

Keywords: :

• acrosome
• glucosylceramide
• glycosphingolipid
• imino sugar
• semen parameters
• sperm morphology
• spermatid
• spermatogenesis

Financial & competing interests disclosure

ACS and FMP are in receipt of a grant from Bayer Schering Pharma AG, Berlin, Germany. The authors would like to acknowledge the support of Oxford GlycoSystems, The Oxford Glycobiology Institute, the NIH/NICHD (ACS and FMP, grant U01 HD045861), Bayer Schering Pharma, and the Wellcome Trust (RM). We also want to thank Wilhelm Bone (Bayer Schering Pharma), Terry Butters, Raymond Dwek and Mark Wormald (Department of Biochemistry, University of Oxford, Oxford, UK), Chia-Chen Chuang (Department of Pharmacology, University of Oxford, Oxford, UK), Harry Moore (University of Sheffield, Sheffield, UK), Richard Oko (Queen‘s University, Kingston, ON, Canada), Ioannis Ragoussis (Wellcome Trust Centre for Human Genetics, Oxford, UK), Roger Sandhoff (German Cancer Research Centre, Heidelberg, Germany), David Smith (Department of Pharmacology), Charlotte M Walden, the MRC Drosophila Cooperative Group (Department of Zoology, University of Oxford, Oxford, UK), and the Electron Microscopy and Microanalysis Group (Department of Materials, University of Oxford, Oxford, UK) for their help with this project. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

ACS and FMP are in receipt of a grant from Bayer Schering Pharma AG, Berlin, Germany. The authors would like to acknowledge the support of Oxford GlycoSystems, The Oxford Glycobiology Institute, the NIH/NICHD (ACS and FMP, grant U01 HD045861), Bayer Schering Pharma, and the Wellcome Trust (RM). We also want to thank Wilhelm Bone (Bayer Schering Pharma), Terry Butters, Raymond Dwek and Mark Wormald (Department of Biochemistry, University of Oxford, Oxford, UK), Chia-Chen Chuang (Department of Pharmacology, University of Oxford, Oxford, UK), Harry Moore (University of Sheffield, Sheffield, UK), Richard Oko (Queen‘s University, Kingston, ON, Canada), Ioannis Ragoussis (Wellcome Trust Centre for Human Genetics, Oxford, UK), Roger Sandhoff (German Cancer Research Centre, Heidelberg, Germany), David Smith (Department of Pharmacology), Charlotte M Walden, the MRC Drosophila Cooperative Group (Department of Zoology, University of Oxford, Oxford, UK), and the Electron Microscopy and Microanalysis Group (Department of Materials, University of Oxford, Oxford, UK) for their help with this project. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.