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 rat. Administration of molinate to rats (40 mg/kg/day for 7 days) caused a distinctive sperm lesion. At higher doses of molinate (140 mg/kg for 7 days) this lesion was accompanied by morphological changes to the testis that were consistent with a delayed release of the late spermatids to the seminiferous tubular lumen, a process controlled by the release of testosterone. In accordance with this, molinate (>/=40 mg/kg) caused a marked decrease in the concentration of circulating and testicular testosterone. The Leydig cells of the testis appear to be the primary target site in that radiolabel from [3H]molinate specifically localized within this cell type. In addition, esterase activity in the Leydig cells was inhibited following molinate administration. In vitro, molinate is a poor inhibitor of esterase activity, whereas molinate sulfoxide, a major metabolite of molinate in rats, and molinate sulfone were shown to be potent inhibitors of this process, suggesting that metabolic activation of molinate is required in vivo. Molinate sulfoxide (>/=10 mg/kg) caused an identical sperm lesion to that of molinate and markedly decreased plasma and testicular testosterone concentration. These effects were not seen with the molinate metabolites 4-hydroxymolinate (10 mg/kg), molinate sulfone (10 mg/kg), and hexamethyleneimine (10 mg/kg). Since the sperm lesion is a secondary event caused by a disruption of spermatogenesis, this would imply that the testis lesion and the reproductive impairment are also a consequence of molinate sulfur oxidation.
Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom.
M K
MK
Ellis
A G
AG
Richardson
J R
JR
Foster
F M
FM
Smith
P S
PS
Widdowson
M J
MJ
Farnworth
R B
RB
Moore
M R
MR
Pitts
G A
GA
Wickramaratne
D000818:Animals; D000988:Antispermatogenic Agents / Q000633:toxicity*; D001381:Azepines / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D002219:Carbamates; D004305:Dose-Response Relationship, Drug; D004950:Esterases / Q000037:antagonists & inhibitors; D006540:Herbicides / Q000633:toxicity*; D006651:Histocytochemistry; D007985:Leydig Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D012451:Safrole / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D012671:Seminiferous Tubules / Q000187:drug effects / Q000378:metabolism; D013087:Spermatids / Q000187:drug effects / Q000378:metabolism; D013094:Spermatozoa / Q000187:drug effects* / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000502:physiology; D013739:Testosterone / Q000097:blood*; D013859:Thiocarbamates
D000988:Antispermatogenic Agents; D001381:Azepines; D002219:Carbamates; D006540:Herbicides; D013859:Thiocarbamates; D013739:Testosterone; C009821:molinate; D004950:Esterases; D012451:Safrole; C005746:sulfoxide