Inhibition of retinoic acid biosynthesis by the bisdichloroacetyldiamine WIN 18,446 markedly suppresses spermatogenesis and alters retinoid metabolism in mice.
Knowledge of the regulation of testicular retinoic acid synthesis is crucial for understanding its role in spermatogenesis. Bisdichloroacetyldiamines strongly inhibit spermatogenesis. We reported previously that one of these compounds, WIN 18,446, potently inhibited spermatogenesis in rabbits by inhibiting retinoic acid synthesis. To understand how WIN 18,446 inhibits retinoic acid synthesis, we characterized its effects on human retinal dehydrogenase ALDH1A2 in vitro as well as its effects on retinoid metabolism in vivo using mice. WIN 18,446 strongly and irreversibly inhibited ALDH1A2 in vitro. In vivo, WIN 18,446 treatment completely abolished spermatogenesis after 4 weeks of treatment and modestly reduced adiposity in mice fed a chow diet. Effects of WIN 18,446 on retinoid concentrations were tissue-dependent. Although lung and liver retinyl ester concentrations were lower in WIN 18,446-treated animals, adipose retinyl ester levels were increased following the treatment. Interestingly, animals treated with WIN 18,446 had significantly higher circulating retinol concentrations compared with control mice. The effect on spermatogenesis by WIN 18,446 was not prevented by simultaneous treatment with retinoic acid, whereas effects on other tissues were partially or completely reversed. Cessation of WIN 18,446 treatment for 4 weeks reversed most retinoid-related phenotypes except for inhibition of spermatogenesis. Our data suggest that WIN 18,446 may be a useful model of systemic acquired retinoic acid deficiency. Given the effects observed in our study, inhibition of retinoic acid biosynthesis may have relevance for the treatment of obesity and in the development of novel male contraceptives.
From the Departments of Comparative Medicine, jpaik@uw.edu.
Jisun
J
Paik
From the Departments of Comparative Medicine.
Michael
M
Haenisch
Urology.
Charles H
CH
Muller
Focused Scientific, Newcastle, Washington 98059.
Alex S
AS
Goldstein
Pharmaceutics, and.
Samuel
S
Arnold
Pharmaceutics, and.
Nina
N
Isoherranen
From the Departments of Comparative Medicine.
Thea
T
Brabb
From the Departments of Comparative Medicine.
Piper M
PM
Treuting
Medicine, University of Washington, Seattle, Washington 98195 and.
John K
JK
Amory
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D003959:Diamines / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004952:Esters / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050697:Retinal Dehydrogenase / Q000378:metabolism; D012176:Retinoids / Q000097:blood / Q000378:metabolism*; D013090:Spermatocytes / Q000187:drug effects / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects*; D013737:Testis / Q000201:enzymology / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014801:Vitamin A / Q000097:blood / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
D003959:Diamines; D004952:Esters; D012176:Retinoids; D014801:Vitamin A; C002491:N,N'-bis(dichloroacetyl)-1,8-octamethylenediamine; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase
ALDH1A2; Adipose Tissue; Animal Models; Bisdichloroacetyldiamine; Fertility; Metabolism; Obesity; Retinoic Acid; Vitamin A