Ellis M K, Richardson A G, Foster J R, Smith F M, Widdowson P S, Farnworth M J, Moore R B, Pitts M R, Wickramaratne G A
Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom.
Toxicol Appl Pharmacol. 1998 Jul;151(1):22-32. doi: 10.1006/taap.1998.8371.
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.
禾草丹会导致雄性大鼠生殖能力受损。给大鼠施用禾草丹（40毫克/千克/天，持续7天）会引发一种独特的精子损伤。在较高剂量的禾草丹（140毫克/千克，持续7天）作用下，这种损伤伴随着睾丸的形态变化，这与晚期精子细胞向曲细精管管腔的延迟释放一致，而这一过程受睾酮释放的控制。据此，禾草丹（≥40毫克/千克）会导致循环和睾丸中睾酮浓度显著降低。睾丸的间质细胞似乎是主要靶位点，因为[3H]禾草丹的放射性标记物特异性地定位于这种细胞类型内。此外，施用禾草丹后，间质细胞中的酯酶活性受到抑制。在体外，禾草丹是一种较弱的酯酶活性抑制剂，而禾草丹亚砜（大鼠体内禾草丹的主要代谢产物）和禾草丹砜被证明是这一过程的有效抑制剂，这表明禾草丹在体内需要代谢活化。禾草丹亚砜（≥10毫克/千克）会引发与禾草丹相同的精子损伤，并显著降低血浆和睾丸中的睾酮浓度。禾草丹的代谢产物4 - 羟基禾草丹（10毫克/千克）、禾草丹砜（10毫克/千克）和六亚甲基亚胺（10毫克/千克）未观察到这些效应。由于精子损伤是精子发生破坏导致的继发事件，这意味着睾丸损伤和生殖功能损害也是禾草丹硫氧化的结果。
