Document Detail


Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis.
MedLine Citation:
PMID:  20705791     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The bisdichloroacetyldiamine WIN 18,446 reversibly inhibits spermatogenesis in many species, including humans; however, the mechanism by which WIN 18,446 functions is unknown. As retinoic acid is essential for spermatogenesis, we hypothesized that WIN 18,446 might inhibit retinoic acid biosynthesis from retinol (vitamin A) within the testes by inhibiting the enzyme aldehyde dehydrogenase 1a2 (ALDH1a2). We studied the effect of WIN 18,446 on ALDH1a2 enzyme activity in vitro, and on spermatogenesis and fertility in vivo, in mature male rabbits for 16 weeks. WIN 18,446 markedly inhibited ALDH1a2 enzyme activity in vitro with an IC(50) of 0.3 μM. In vivo, the oral administration of 200 mg/kg WIN 18,446 to male rabbits for 16 weeks significantly reduced intratesticular concentrations of retinoic acid, severely impaired spermatogenesis, and caused infertility. Reduced concentrations of intratesticular retinoic acid were apparent after only 4 weeks of treatment and preceded the decrease in sperm counts and the loss of mature germ cells in tissue samples. Sperm counts and fertility recovered after treatment was discontinued. These findings demonstrate that bisdichloroacetyldiamines such as WIN 18,446 reversibly suppress spermatogenesis via inhibition of testicular retinoic acid biosynthesis by ALDH1a2. These findings suggest that ALDH1a2 is a promising target for the development of a reversible, nonhormonal male contraceptive.
Authors:
John K Amory; Charles H Muller; Jakob A Shimshoni; Nina Isoherranen; Jisun Paik; Jan S Moreb; David W Amory; Ryan Evanoff; Alex S Goldstein; Michael D Griswold
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-08-12
Journal Detail:
Title:  Journal of andrology     Volume:  32     ISSN:  1939-4640     ISO Abbreviation:  J. Androl.     Publication Date:    2011 Jan-Feb
Date Detail:
Created Date:  2010-12-20     Completed Date:  2011-03-28     Revised Date:  2014-05-14    
Medline Journal Info:
Nlm Unique ID:  8106453     Medline TA:  J Androl     Country:  United States    
Other Details:
Languages:  eng     Pagination:  111-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Contraceptive Agents, Male / pharmacology
Diamines / pharmacology*
Male
Rabbits
Retinal Dehydrogenase / antagonists & inhibitors*
Spermatogenesis / drug effects*
Testis / drug effects*
Tretinoin / antagonists & inhibitors*,  metabolism
Grant Support
ID/Acronym/Agency:
R01GM081569-02S1/GM/NIGMS NIH HHS; U01 HD060408/HD/NICHD NIH HHS; U01 HD060488/HD/NICHD NIH HHS; U54 HD042454/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Contraceptive Agents, Male; 0/Diamines; 1477-57-2/N,N'-bis(dichloroacetyl)-1,8-octamethylenediamine; 5688UTC01R/Tretinoin; EC 1.2.1.36/Retinal Dehydrogenase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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