The sensitivity of murine spermiogenesis to miglustat is a quantitative trait: a pharmacogenetic study

Abstract

Background: A major event in the post-meiotic development of male germ cells is the formation of the acrosome. This process can be perturbed in C57BL/6 mice by administration of the small molecule miglustat (N-butyldeoxynojirimycin, NB-DNJ). The miglustat-treated mice produce morphologically abnormal spermatozoa that lack acrosomes and are poorly motile. In C57BL/ 6 mice, miglustat can be used to maintain long-term reversible infertility. In contrast, when miglustat was evaluated in normal men, it did not affect spermatogenesis. To gain more insight into this species difference we have now evaluated the reproductive effects of miglustat in rabbits, in multiple mouse strains and in interstrain hybrid mice.

Accumulation of Glucosylceramide in Murine Testis, Caused by Inhibition of β-Glucosidase 2

“…Therefore impairment of spermatogenesis has been observed in mice that have, on the one hand, at least in part a C57BL/6 background, and, on the other hand, diminished GBA2 activity (through disruption of the GBA2 gene or via administration of imino sugars). We have found that NB-DNJ-treated inbred mice with genetic backgrounds unrelated to C57BL/6 have levels of testicular GlcCer as high as in C57BL/6 mice, but without a reproductive phenotype (23). We have also seen that NB-DNJ elevates GlcCer in FVB/N x C57BL/6 hybrid mice, whereas only in a minority of these hybrids is spermatogenesis affected (23).…”

“…We have found that NB-DNJ-treated inbred mice with genetic backgrounds unrelated to C57BL/6 have levels of testicular GlcCer as high as in C57BL/6 mice, but without a reproductive phenotype (23). We have also seen that NB-DNJ elevates GlcCer in FVB/N x C57BL/6 hybrid mice, whereas only in a minority of these hybrids is spermatogenesis affected (23). Thus the consequence of GBA2 deficiency and GBA2 inhibition through lowdose imino sugar treatment seems universal (higher level GlcCer), but the impact of this alteration on male germ cell development is dependent on genetic background.…”

“…We have shown that the reproductive consequences of NB-DNJ are much milder in male mice of various inbred strains from the Swiss/Castle lineages, judging by the acrosomal and nuclear morphology of their spermatozoa. Also, after NB-DNJ administration, FVB/N, DBA/2, and 129S1/ SvImJ males were equally fertile as controls in natural mating tests (23).…”

“…The reproductive effect of NB-DNJ in male inbred mice is straindependent (23). We have shown that the reproductive consequences of NB-DNJ are much milder in male mice of various inbred strains from the Swiss/Castle lineages, judging by the acrosomal and nuclear morphology of their spermatozoa.…”

“…Alternatively, the possibility could be considered that in mouse strains, which do not become infertile from NB-DNJ, the drug causes GlcCer to increase, but without this being of consequence for spermatogenesis. Therefore, we administered NB-DNJ to males of 11 strains of mice that can be divided into three groups on the basis of the impact of NB-DNJ on the morphology of their spermatozoa, having a high, medium, or low percentage of grossly abnormal acrosome-less spermatozoa (23). In strains of mice 4 R. Sandhoff and A. C. van der Spoel, submitted for publication.…”