title: 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 deformities.
abstract: 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, Sr(2+). Oocytes injected with the misshapen spermatozoa from NB-DNJ- and NB-DGJ-treated mice developed (with or without Sr(2+) 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.
authors.affiliation: Institute for Biogenesis Research, University of Hawaii School of Medicine, Honolulu, Hawaii 96822, USA.
authors.forename: Ryota
authors.initials: R
authors.lastname: Suganuma
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Walden
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Yanagimachi
authors.forename: Aarnoud C
authors.initials: AC
authors.lastname: van der Spoel
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000478:Alkylation; D000818:Animals; D002241:Carbohydrates; D003272:Contraceptive Agents, Male / Q000494:pharmacology*; D004220:Disulfides / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000187:drug effects / Q000235:genetics; D005307:Fertilization in Vitro; D007097:Imines; D007248:Infertility, Male / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011247:Pregnancy; D011256:Pregnancy Outcome; D011479:Protamines / Q000378:metabolism; D013094:Spermatozoa / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D002241:Carbohydrates; D003272:Contraceptive Agents, Male; D004220:Disulfides; D007097:Imines; D011479:Protamines; D013107:Sphingolipids; D017485:1-Deoxynojirimycin; C059896:miglustat; C090092:migalastat