Collaborative work to determine an optimal administration period and optimal parameters for detection of effects on male fertility in rats--male reproductive toxicity study of haloperidol.

Abstract

Haloperidol, a neuroleptic, was orally administered at 0, 3, 10, 30 and 60 mg/kg/day in a 4-week dosing study, and 0, 3, 10 and 30 mg/kg/day in a 9-week dosing study, to Sprague-Dawley male rats which were then sacrificed for histopathological examination or mated with untreated females. The males in the mating groups were continuously treated during the mating period. Sperm positive females were sacrificed on day 20 of gestation. The males in the histopathology groups were sacrificed after 4- or 9-week dosing and their testes were fixed in Bouin's fluid and sections stained with HE or PAS. The mated males were sacrificed and reproductive organ weights were determined. At 3 mg/kg or more, reduced spontaneous motor activity was observed and body weights were lowered. The absolute weight of testes was decreased with 60 mg/kg in the 4-week dosing study, and was decreased with 10 and 30 mg/kg in the 9-week dosing study. However, the relative weight was increased or showed a tendency to increase. In the 4-week dosing study, decrease in the fertility index with 60 mg/kg and increase in pre-implantation loss with 30 mg/kg or more were noted. However, there were no adverse effects on the copulation index in any of the treated groups. The males given 60 mg/kg showed slight changes in the testes (necrosis of pachytene spermatocytes in seminiferous tubules of stage VII, exfoliation of round spermatids in the lumina and atrophy of Leydig cells) and seminal vesicles (atrophy of epithelial cells). Atrophy of Leydig cells was also observed at 30 mg/kg in the 4-week dosing study. In the 9-week dosing study, neither male reproductive ability nor histopathological parameters were affected by haloperidol up to 30 mg/kg. From the results detailed above, it may be concluded that 4-weeks dosing before mating is suitable for detection of effects of haloperidol on male reproductive ability, and that histopathological changes together provide an optimal parameter for predicting male reproductive disorders.