Long-term effects of lonidamine on mouse testes

Lonidamine (LND) [1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid] is a well-known antispermatogenic drug. The aim of this study was to identify its possible long-term sequelae on the reproductive system of mice as compared with rats, where most data have been obtained until now. Sexually mature CD1 male mice were administered a single dose of LND (200 mg/kg bw by gavage) and killed 24 and 48 h, 6 days and 2, 4 and 8 weeks after the treatment. Testes were collected, weighed and (1) fixed in Bouin's solution for histological analysis or (2) reduced to monocellular suspensions and ethanol fixed to undergo flow cytometry (FCM) DNA content analysis. No effect on body weight and/or food consumption was observed in the treated group in comparison with the control group. Testicular weight was significantly reduced 24 h after the treatment. Reduced seminiferous epithelium with a progressive lack of intercellular cohesion and marked depletion of spermatids, infiltration of granulocytes, desquamation into the tubular lumen and increased intertubular spaces were present by 24 h after the treatment and persisted to a marked degree at 48 h, 6 days and 2 and 4 weeks up to a marked degeneration of tubular structures with absence of spermatogenesis. The same effects, albeit with a moderate severity, were still present 8 weeks after the treatment. As also detected by FCM, primary spermatocytes appeared to be the main cellular target. Sertoli and Leydig cells were remarkably spared. The histological findings are consistent with those previously observed in rats and point out that testicular damage may persist for several weeks after a single-dose administration. Findings are discussed in comparison with testicular toxicity elicited by other xenobiotics.