Studies to elucidate the mechanism of fenarimol-induced infertility in male rats

Fenarimol (alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5- pyrimidinemethanol a pyrimidine carbinol fungicide, caused a dose-related decrease in male fertility in Wistar rats. The effect was particularly evident in the anatomically normal progeny of dams treated with fenarimol throughout gestation and lactation. Based on the observation that the infertility was associated with the absence of vaginal sperm at the time of mating, the effect appeared to be the result of an absence of male sexual behavior. Fenarimol does not readily cross the placenta but does concentrate in milk, reaching three- to fivefold higher concentrations than those observed in the maternal plasma. These results suggest that fenarimol might be acting to block the perinatal development of male patterns of sexual behavior which involves the action of gonadal steroids within the central nervous system (CNS). To test this hypothesis, [14C]fenarimol was administered to dams and the radioactivity measured in the brains of the neonates. Radioactivity in the hypothalamus was three- to fourfold higher and the half-life four times longer than that observed in the remainder of the brain. Since the hypothalamus is believed to play a key role in the development and expression of male sexual behavior, it appears likely that fenarimol is acting centrally to decrease male sexual behavior, thereby decreasing male fertility.