Mohr U, Dasenbrock C, Tillmann T, Kohler M, Kamino K, Hagemann G, Morawietz G, Campo E, Cazorla M, Fernandez P, Hernandez L, Cardesa A, Tomatis L
Institut für Experimentelle Pathologie, Medizinische Hochschule Hannover, Germany.
Carcinogenesis. 1999 Feb;20(2):325-32. doi: 10.1093/carcin/20.2.325.
A lifetime experiment using 4279 CBA/J mice was carried out to investigate whether the pre-conceptual exposure of sperm cells to X-ray radiation or urethane would result in an increased cancer risk in the untreated progeny, and/or increased susceptibility to cancer following exposure to a promoting agent. The study consisted of four main groups, namely a control group (saline), a urethane group (1 mg/g body wt) and two X-ray radiation groups (1 Gy, 2 Gy). At 1, 3 and 9 weeks after treatment, the males of these four parental groups were mated with untreated virgin females. The offspring of each parental group was divided into two subgroups: one received s.c. urethane (0.1 mg/g body wt once) as a promoter, the other saline, at the age of 6 weeks. All animals were evaluated for the occurrence of tumours. K-ras oncogene and p53 tumour suppressor gene mutations were investigated in frozen lung tumour samples. The female offspring of male parents exposed to X-rays 1 week before their mating showed a trend towards a higher tumour incidence of the haematopoietic system than the F1 controls. In addition, a higher percentage of bronchioloalveolar adenocarcinomas in male offspring born to irradiated paternals mated 1 week after X-ray treatment points to a plausible increased sensitivity of post-meiotic germ cell stages towards transgenerational carcinogenic effects. On the other hand, no increased tumour incidence and malignancy were observed in the offspring born to irradiated paternals mated 3 and 9 weeks after X-ray treatment. Paternal urethane treatment 1, 3 and 9 weeks prior to conception did not result in significantly altered incidence or malignancy of tumours of the lung, liver and haematopoietic tissue in the offspring. K-ras mutations increased during tumour progression from bronchioloalveolar hyperplasia to adenoma. Codon 61 K-ras mutations were more frequent in lung tumours of urethane-promoted progeny from irradiated parents than from control parents. P53 mutations were absent from these lung alterations.
利用4279只CBA/J小鼠进行了一项终生实验，以研究精子细胞在受孕前暴露于X射线辐射或氨基甲酸乙酯是否会导致未处理后代的癌症风险增加，和/或在暴露于促癌剂后对癌症的易感性增加。该研究包括四个主要组，即对照组（生理盐水）、氨基甲酸乙酯组（1毫克/克体重）和两个X射线辐射组（1戈瑞、2戈瑞）。在治疗后1周、3周和9周，这四个亲代组的雄性与未处理的处女雌性交配。每个亲代组的后代分为两个亚组：一组在6周龄时接受皮下注射氨基甲酸乙酯（0.1毫克/克体重一次）作为促癌剂，另一组接受生理盐水。评估所有动物的肿瘤发生情况。在冷冻的肺肿瘤样本中研究K-ras癌基因和p53肿瘤抑制基因突变。在交配前1周暴露于X射线的雄性亲代的雌性后代显示，其造血系统肿瘤发生率有高于F1对照组的趋势。此外，在X射线治疗后1周交配的受辐射父本所生的雄性后代中，细支气管肺泡腺癌的比例更高，这表明减数分裂后生殖细胞阶段对跨代致癌作用的敏感性可能增加。另一方面，在X射线治疗后3周和9周交配的受辐射父本所生的后代中，未观察到肿瘤发生率和恶性程度增加。受孕前1周、3周和9周父本接受氨基甲酸乙酯治疗，并未导致后代肺、肝和造血组织肿瘤的发生率或恶性程度发生显著改变。从细支气管肺泡增生发展到腺瘤的肿瘤进展过程中，K-ras突变增加。与对照亲本相比，受辐射亲本的氨基甲酸乙酯促进后代的肺肿瘤中，密码子61的K-ras突变更为频繁。这些肺病变中不存在p53突变。
