THE REPRODUCTIVE TOXICITY OF MOLINATE AND METABOLITES TO THE MALE-RAT- EFFECTS ON TESTOSTERONE AND SPERM MORPHOLOGY

Molinate causes an impairment in reproductive capability in the male r at. Administration of molinate to rats (40 mg/kg/day for 7 days) cause d a distinctive sperm lesion. At higher doses of molinate (140 mg/kg f or 7 days) this lesion was accompanied by morphological changes to the testis that were consistent with a delayed release of the late sperma tids to the seminiferous tubular lumen, a process controlled by the re lease of testosterone. In accordance with this, molinate (greater than or equal to 40 mg/kg) caused a marked decrease in the concentration o f circulating and testicular testosterone. The Leydig cells of the tes tis appear to be the primary target site in that radiolabel from [H-3] molinate specifically localized within this cell type. In addition, es terase activity in the Leydig cells was inhibited following molinate a dministration. In vitro, molinate is a poor inhibitor of esterase acti vity, whereas molinate sulfoxide, a major metabolite of molinate in ra ts, and molinate sulfone were shown to be potent inhibitors of this pr ocess, suggesting that metabolic activation of molinate is required in vivo. Molinate sulfoxide (greater than or equal to 10 mg/kg) caused a n identical sperm lesion to that of molinate and markedly decreased pl asma and testicular testosterone concentration. These effects were not seen with the molinate metabolites 4-hydroxymolinate (10 mg/kg), moli nate sulfone (10 mg/kg), and hexamethyleneimine (10 mg/kg). Since the sperm lesion is a secondary event caused by a disruption of spermatoge nesis, this would imply that the testis lesion and the reproductive im pairment are also a consequence of molinate sulfur oxidation. (C) 1998 Academic Press.