TESTICULAR TOXICITY OF MOLINATE IN THE RAT - METABOLIC-ACTIVATION VIASULFOXIDATION

Molinate is a thiocarbamate herbicide widely used in rice culture. Stu dies conducted for regulatory purposes have indicated that molinate ex posure causes male reproductive damage in rats. The present study desc ribes the testicular lesion after administration of single doses of mo linate. The hypothesis that a metabolite of molinate is responsible fo r testicular toxicity was also investigated. Testicular damage was eva luated histopathologically in Sprague-Dawley rats 48 h and 1, 2, and 3 weeks after administration of molinate (100-400 mg/kg ip). No testicu lar damage was seen at any time point at the 100 mg/kg dose level. Dam age was first seen 1 week after 200 mg/kg and 48 h after 400 mg/kg. Th e lesion was characterized by Sertoli cell vacuolation, failed spermia tion, and phagocytosis of spermatids particularly evident at Stages X and XI. With increasing time, damage progressed until disorganization of the seminiferous epithelium was extensive, multinucleated giant cel ls were numerous, and neither spermatozoa nor late step spermatids wer e present. At 3 weeks after administration of the two higher-dose leve ls, germ cells in the seminiferous tubules were almost completely abse nt. Administration of the sulfoxide metabolite of molinate (200 mg/kg ip) caused testicular damage similar in severity to that seen at the 4 00 mg/kg dose level for the parent compound, indicating that it was mo re potent as a testicular toxicant. In vitro metabolism studies using liver and testis microsomes found that the major metabolite in both pr eparations was molinate sulfoxide. Testis microsomes produced only sli ghtly less sulfoxide when compared with liver microsomes. Molinate was also metabolized via ring hydroxylation to form small amounts of hydr oxymolinate. The amount of hydroxymolinate was substantially less in t estis microsomes. Overall, these data indicate that sulfoxidation of m olinate plays a role in molinate-induced testicular toxicity. Moreover , molinate is metabolized readily by both liver and testis microsomal enzymes, suggesting that the molinate toxic metabolite could be formed in the testis in close proximity to its site of action. (C) 1998 Acad emic Press.