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Overview
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Background
WIN 18446 is a bis-(dichloroacetyl)-diamine which inhibits aldehyde dehydrogenase 1a2 (ALDH1a2), with IC50 value of 300 nM [1].
ALDH1a2, expressed almost exclusively in the testes, localizes to developing germ cells within the seminiferous tubules and strongly binds retinol, but does not recognize acetaldehyde as a substrate, suggesting that ALDH1a2 functions in testicular retinoic acid biosynthesis [1].
In whole testes or germ cells isolated from mice at 2 days postpartum, WIN 18,446 alone (1 μM) or in combination with retinol significantly reduced the expression of Stra8, a marker for retinoic acid activity [2].
In male rabbits, oral administration of WIN 18446 at 200 mg/kg for 16 weeks substantially reduced intratesticular concentrations of retinoic acid, significantly impaired spermatogenesis, and resulted in infertility. Reduced concentrations of intratesticular retinoic acid became obvious 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 [1].[1]. Amory J K, Muller C H, Shimshoni J A, et al. Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis. Journal of Andrology, 2011, 32(1): 111-119.
[2]. Hogarth C A, Evanoff R, Snyder E, et al. Suppression of Stra8 expression in the mouse gonad by WIN 18,446. Biology of Reproduction, 2011, 84(5): 957-965.
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