Moore F R, Urda G A, Krishna G, Theiss J C
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105, USA.
Mutat Res. 1996 Jan;367(1):33-41. doi: 10.1016/s0165-1218(96)90019-1.
Selenium monosulfide (SeS) was reported to be carcinogenic to livers of male and female rats and livers and lungs of female mice. However, its genotoxicity profile in short-term assays is somewhat equivocal. A multiple endpoint/multiple tissue approach to short-term genetic toxicity testing has been developed in our laboratory. In the present paper, the effect of SeS in in vivo and in vivo/in vitro micronucleus and chromosome aberration assays in rat bone marrow and spleen are reported. In the in vivo assay, small but statistically significant increases in bone marrow micronucleated polychromatic erythrocytes (MNPCEs) were observed 24 h after treatment of rats with 50 mg/kg SeS and 48 h after treatment with 12.5 mg/kg. A significant decrease in the PCE/total erythrocyte (TE) ratio, indicative of cytotoxicity, was observed at the 50 mg/kg dose at the 24-h timepoint. In spleen, no increases in MNPCEs or decreases in the PCE/TE ratios were observed. No evidence of a significant increase in aberrations was observed in bone marrow or spleen. In the in vivo/in vitro assay, no increase in micronucleated binucleated cells or cells with aberrations was observed in SeS-treated rats. The small but statistically significant increases in MN observed in the in vivo study are considered likely not to be biologically significant since no dose-response was observed and all the values obtained were within historical control range in our laboratory. Given the overall genetic toxicity profile of SeS, it appears that SeS may be a weak mutagen and that differences between testing protocols may be very important in determining whether or not it is found to be negative or positive. Histological evidence was obtained in this study that suggests that the liver is the acute target organ of SeS in rats. Given the fact that SeS is selectively hepatocarcinogenic, we are currently testing the hypothesis that the genotoxicity of SeS in rats may be more readily detectable in liver than in bone marrow or spleen.
据报道，一硫化硒（SeS）对雄性和雌性大鼠的肝脏以及雌性小鼠的肝脏和肺具有致癌性。然而，其在短期试验中的遗传毒性情况有些模糊。我们实验室已开发出一种用于短期遗传毒性测试的多终点/多组织方法。在本文中，报告了SeS在大鼠骨髓和脾脏的体内及体内/体外微核和染色体畸变试验中的作用。在体内试验中，用50mg/kg SeS处理大鼠24小时后以及用12.5mg/kg处理48小时后，观察到骨髓微核多染红细胞（MNPCEs）有小幅但具有统计学意义的增加。在24小时时间点，50mg/kg剂量组观察到PCE/总红细胞（TE）比值显著降低，表明存在细胞毒性。在脾脏中，未观察到MNPCEs增加或PCE/TE比值降低。在骨髓或脾脏中未观察到畸变有显著增加的证据。在体内/体外试验中，在经SeS处理的大鼠中未观察到微核双核细胞或有畸变细胞增加。在体内研究中观察到的MN小幅但具有统计学意义的增加被认为可能没有生物学意义，因为未观察到剂量反应，且获得的所有值都在我们实验室的历史对照范围内。鉴于SeS的总体遗传毒性情况，似乎SeS可能是一种弱诱变剂，并且测试方案之间的差异在确定其结果为阴性或阳性时可能非常重要。本研究获得的组织学证据表明，肝脏是SeS在大鼠中的急性靶器官。鉴于SeS具有选择性肝致癌性，我们目前正在测试这样一种假设，即SeS在大鼠中的遗传毒性在肝脏中可能比在骨髓或脾脏中更容易检测到。
