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

Suganuma, Ryota; Walden, Charlotte M.; Butters, Terry D.; Platt, Frances M.; Dwek, Raymond A.; Yanagimachi, Ryuzo; Spoel, Aarnoud C. van der

doi:10.1095/biolreprod.104.036053

Cited by 54 publications

(43 citation statements)

References 51 publications

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“…Similar levels of GlcCer were achieved both with low drug doses (Ͻ15 mg/kg/day for NB-DNJ and Ͻ300 mg/kg/day for NB-DGJ), and with higher doses, whereas C57BL/6 mice only become infertile at doses of at least 15 mg/kg/day miglustat (19) or 150 mg/kg/ day NB-DGJ (21). Nevertheless, for both drugs the minimal dose required to induce infertility coincided with the dose that maximally elevated GlcCer.…”

Section: Discussionmentioning

confidence: 58%

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

Walden

Sandhoff

Chuang

et al. 2007

Journal of Biological Chemistry

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One of the hallmarks of male germ cell development is the formation of a specialized secretory organelle, the acrosome. This process can be pharmacologically disturbed in C57BL/6 mice, and thus infertility can be induced, by small molecular sugar-like compounds (alkylated imino sugars). Here the biochemical basis of this effect has been investigated. Our findings suggest that in vivo alkylated imino sugars primarily interact with the non-lysosomal glucosylceramidase. This enzyme cleaves glucosylceramide into glucose and ceramide, is sensitive to imino sugars in vitro, and has been characterized as ␤-glucosidase 2 (GBA2). Imino sugars raised the level of glucosylceramide in brain, spleen, and testis, in a dose-dependent fashion. In testis, multiple species of glucosylceramide were similarly elevated, those having long acyl chains (C16 -24), as well as those with very long polyunsaturated acyl chains (C28 -30:5). Both of these GlcCer species were also increased in the testes from GBA2-deficient mice. When considering that the very long polyunsaturated sphingolipids are restricted to germ cells, these results indicate that in the testis GBA2 is present in both somatic and germ cells. Furthermore, in all mouse strains tested imino sugar treatment caused a rise in testicular glucosylceramide, even in a number of strains, of which the males remain fertile after drug administration. Therefore, it appears that acrosome formation can be derailed by accumulation of glucosylceramide in an extralysosomal localization, and that the sensitivity of male germ cells to glucosylceramide is genetically determined.

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Section: Discussionmentioning

confidence: 58%

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

Walden

Sandhoff

Chuang

et al. 2007

Journal of Biological Chemistry

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“…The bile acid glucosidase activity of GBA2 is inhibited by iminosugars such as 1-deoxynojirimycin (10,12), and administration of alkylated iminosugars to mice causes male infertility and globozoospermia (22)(23)(24). 1-Deoxynojirimycin inhibits glucosidases involved in the processing of asparagine-linked carbohydrates attached to proteins as well as those involved in the biosynthesis of glycolipids (25,26).…”

Section: Figurementioning

confidence: 99%

Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility

Yildiz¹,

Matern²,

Thompson³

et al. 2006

J. Clin. Invest.

199

231

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β-Glucosidase 2 (GBA2) is a resident enzyme of the endoplasmic reticulum thought to play a role in the metabolism of bile acid-glucose conjugates. To gain insight into the biological function of this enzyme and its substrates, we generated mice deficient in GBA2 and found that these animals had normal bile acid metabolism. Knockout males exhibited impaired fertility. Microscopic examination of sperm revealed large round heads (globozoospermia), abnormal acrosomes, and defective mobility. Glycolipids, identified as glucosylceramides by mass spectrometry, accumulated in the testes, brains, and livers of the knockout mice but did not cause obvious neurological symptoms, organomegaly, or a reduction in lifespan. Recombinant GBA2 hydrolyzed glucosylceramide to glucose and ceramide; the same reaction catalyzed by the β-glucosidase acid 1 (GBA1) defective in subjects with the Gaucher's form of lysosomal storage disease. We conclude that GBA2 is a glucosylceramidase whose loss causes accumulation of glycolipids and an endoplasmic reticulum storage disease.

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“…These results show that SrCl 2 treatment is useful for activating human oocytes that frequently fail to fertilize in ICSI. In addition, calcium oscillation patterns with SrCl 2 treatment appear closer to the pattern which occurs with spontaneous fertilization than artificial activation by calcium ionophore [31]. However, it is not known whether or not SrCl 2 is as useful for oocyte activation as ICSI with frozen-thawed testicular spermatozoa.…”

Section: Discussionmentioning

confidence: 73%

Live birth after SrCl2 oocyte activation in previous repeated failed or low fertilization rates after ICSI of frozen-thawed testicular spermatozoa: case report

Kim

Choi

Yang

et al. 2012

J Assist Reprod Genet

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Purpose To report a live birth resulting after strontium chloride (SrCl 2 ) oocyte activation in a couple with complete fertilization failure or low fertilization rates following intracytoplasmic sperm injection (ICSI) of frozen-thawed testicular spermatozoa. Methods The couple underwent ICSI of frozen-thawed testicular spermatozoa. After ICSI, the oocytes were artificially activated by SrCl 2 because the results of fertilization were not satisfactory in the previous cycles. The main outcome measures were fertilization, pregnancy, and birth. Results In the first and second cycles performed previously at another clinic, fertilization rates were 9.1 % and 0.0 %, respectively. In the third cycle, 31 metaphase II oocytes were retrieved. After sperm injection, all of the oocytes were stimulated using SrCl 2 for activation. Sixteen oocytes were fertilized (51.6 %), and a single embryo was transferred into the uterus on Day 3. A healthy girl weighing 2750 g was born at 40 weeks of gestation by caesarean section. Conclusions This result suggests that SrCl 2 could be useful for oocyte fertilization in case of repeated complete fertilization failure or low fertilization rates following ICSI of frozen-thawed testicular spermatozoa.

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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

Cited by 54 publications

References 51 publications

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

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

Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility

Live birth after SrCl2 oocyte activation in previous repeated failed or low fertilization rates after ICSI of frozen-thawed testicular spermatozoa: case report

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