Hong Hue-Hua L, Houle Christopher D, Ton Thai-Vu T, Sills Robert C
Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
Toxicol Pathol. 2007 Jan;35(1):81-5. doi: 10.1080/01926230601063839.
Ethylene oxide is a multisite carcinogen in rodents and classified as a human carcinogen by the National Toxicology Program. In 2-year mouse studies, ethylene oxide (EO) induced lung, Harderian gland (HG), and uterine neoplasms. We evaluated representative EO-induced and equivalent spontaneous neoplasms for K-ras mutations in codons 12, 13, and 61. K-ras mutations were identified in 100% (23/23) of the EO-induced lung neoplasms and 25% (27/108) of the spontaneous lung neoplasms. Codon 12 G to T transversions were common in EO-induced lung neoplasms (21/23) but infrequent in spontaneous lung neoplasms (1/108). K-ras mutations were found in 86% (18/21) of the EO-induced HG neoplasms and 7% (2/27) of the spontaneous HG neoplasms. Codon 13 G to C and codon 12 G to T transversions were predominant in the EO-induced HG neoplasms but absent in spontaneous HG neoplasms (0/27). K-ras mutations occurred in 83% (5/6) of the EO-induced uterine carcinomas and all were codon 13 C to T transitions. These data show a strong predilection for development of K-ras mutations in EO-induced lung, Harderian gland, and uterine neoplasms. This suggests that EO specifically targets the K-ras gene in multiple tissue types and that this event is a critical component of EO-induced tumorigenesis.
环氧乙烷是啮齿动物的多部位致癌物，被美国国家毒理学计划列为人类致癌物。在为期两年的小鼠研究中，环氧乙烷（EO）诱发了肺部、哈氏腺（HG）和子宫肿瘤。我们评估了具有代表性的EO诱发肿瘤和等效的自发性肿瘤中密码子12、13和61的K-ras突变情况。在100%（23/23）的EO诱发肺部肿瘤和25%（27/108）的自发性肺部肿瘤中发现了K-ras突变。密码子12由G到T的颠换在EO诱发的肺部肿瘤中很常见（21/23），但在自发性肺部肿瘤中很少见（1/108）。在86%（18/21）的EO诱发的HG肿瘤和7%（2/27）的自发性HG肿瘤中发现了K-ras突变。密码子13由G到C和密码子12由G到T的颠换在EO诱发的HG肿瘤中占主导地位，但在自发性HG肿瘤中未出现（0/27）。K-ras突变发生在83%（5/6）的EO诱发的子宫癌中，且均为密码子13由C到T的转换。这些数据表明，在EO诱发的肺部、哈氏腺和子宫肿瘤中，K-ras突变的发生具有强烈的倾向性。这表明EO在多种组织类型中特异性地靶向K-ras基因，并且这一事件是EO诱发肿瘤发生的关键组成部分。
