Sotomayor R E, Sega G A, Kadlubar F
Food and Drug Administration, Center for Food Safety and Applied Nutrition, Laurel, Maryland 20708.
Environ Mol Mutagen. 1994;24(1):68-74. doi: 10.1002/em.2850240109.
The extent and persistence of DNA damage and repair were investigated in mouse spermatogenic cells exposed in vivo to urethane (ethyl carbamate, EC). Adult male mice exposed to [3H]EC at 10-1,000 mg/kg were sacrificed 12 hr later. EC/metabolite binding to liver and testicular DNA and to sperm heads from the vasa deferentia was measured. Other male mice were exposed to EC at 50-750 mg/kg, and unscheduled DNA synthesis (UDS) induction was investigated in early spermatid stages. Similar experiments were conducted with vinyl carbamate (VC; putative EC metabolite) at 10-75 mg/kg. [3H]EC bound to liver and testicular DNA and to whole sperm heads. Testicular DNA binding increased linearly with dose, although binding was at least 2 orders of magnitude lower than with liver DNA. Sperm head binding also increased linearly with dose. Dose response studies with the UDS assay showed that EC and VC induced a small but significant increase of the UDS response in early spermatid stages. However, the induced UDS responses were quite variable and did not consistently increase with the administered dose. To determine the time kinetics of UDS induction, [3H]dThd was injected at various times after treatment with 500 mg/kg of EC or 60 mg/kg of VC. A slight but significant UDS increase was observed 4 hr after treatment with EC but not with VC. Overall, these results suggest that EC metabolites bind to testis DNA and cause low-level DNA damage in mouse spermatogenic cells. This type of DNA damage apparently does not have significant genetic consequences.
研究了体内暴露于氨基甲酸乙酯（尿烷，EC）的小鼠生精细胞中DNA损伤和修复的程度及持续性。成年雄性小鼠经10 - 1000 mg/kg的[³H]EC处理后12小时处死。测定了EC/代谢物与肝脏和睾丸DNA以及输精管精子头部的结合情况。其他雄性小鼠经50 - 750 mg/kg的EC处理，研究了早期精子细胞阶段的非程序性DNA合成（UDS）诱导情况。对10 - 75 mg/kg的氨基甲酸乙烯酯（VC；推测的EC代谢物）进行了类似实验。[³H]EC与肝脏和睾丸DNA以及整个精子头部结合。睾丸DNA结合量随剂量呈线性增加，尽管其结合量比肝脏DNA至少低2个数量级。精子头部结合量也随剂量呈线性增加。UDS试验的剂量反应研究表明，EC和VC在早期精子细胞阶段诱导UDS反应有小幅但显著的增加。然而，诱导的UDS反应变化很大，并不随给药剂量持续增加。为确定UDS诱导的时间动力学，在用500 mg/kg的EC或60 mg/kg的VC处理后的不同时间注射[³H]dThd。EC处理后4小时观察到UDS有轻微但显著的增加，而VC处理后未观察到。总体而言，这些结果表明EC代谢物与睾丸DNA结合并在小鼠生精细胞中造成低水平的DNA损伤。这种类型的DNA损伤显然没有显著的遗传后果。
