Suppression of spermatogenesis and chronic toxicity in men by a new series of bis(dichloroacetyl) diamines

Short-term effects of N'N-bis(dichloroacetyl)-1,8-octamethylenediamine (WIN 18446) on the testes, selected sperm parameters and fertility of male CBA mice

“…Full recovery to normal seminiferous tubule diameters was attained after 42 days of WIN treatment followed by 42 days of withdrawal. These ndings conform to the seminiferous tubule diameter reductions in the rat (Beyler et al 1961, Heller et al 1961, Drobeck & Coulston 1962, Kar et al 1966 and in the mouse (Singh & Dominic 1995).…”

“…Studies of the rat model have indicated that spermatogenic arrest is evident (Coulston et al 1960, Drobeck & Coulston 1962, Kar et al 1966, Reddy & Svoboda 1967. WIN administered to humans produces an effective reduction in the numbers of ejaculated sperm and an alteration in their morphology (Heller et al 1961(Heller et al , 1963. In mice, WIN affects rst the spermatids then the spermatocytes, with severe atrophic changes in the seminiferous tubules (Singh & Dominic 1995).…”

Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice

“…9C). We believe that this is likely due to insufficient recovery time from the WIN 18,446 treatment as we and others have shown that the blockage in spermatogenesis is reversible given sufficient time (13,14,35). In our previous study with rabbits, we observed mature spermatozoa in ejaculates after 16 weeks of drug cessation (13), and other studies reported recovery times of greater than 4 weeks in various animals, including humans (14,35,36).…”

“…It is known that WIN 18,446 also inhibits another aldehyde dehydrogenase, ALDH2 (the main enzyme involved in alcohol metabolism), causing the "disulfiram reaction" when a subject consumes alcohol while taking WIN 18,446 that is the basis for aversion therapy in treatment of alcoholism (14). To determine whether the mechanism of inhibition of ALDHs by WIN 18,446 is similar to that of disulfiram, we compared disulfiram and WIN 18,446 for their inhibitory effects on ALDH1A2.…”

“…The effect of WIN 18,446 on spermatogenesis is reversible in that cessation of drug administration results in complete recovery of spermatogenesis (13). Although the reversible nature of WIN 18,446 inhibition of spermatogenesis is promising for its use as an oral contraceptive (14), its broad inhibitory effects on other isozymes of aldehyde dehydrogenase, such as ALDH2, the enzyme important for the metabolism of alcohol, prevents it from being used for such a purpose (13). However, strong inhibitory effects of WIN 18,446 on ALDH1A2 enzymes provide an opportunity to address some of the questions regarding effects of retinoic acid synthesis on various biological functions, including spermatogenesis and adipogenesis.…”