Anderson L M, Hagiwara A, Kovatch R M, Rehm S, Rice J M
Division of Cancer Etiology, National Cancer Institute, Frederick, Maryland 21701.
Fundam Appl Toxicol. 1989 Apr;12(3):604-20. doi: 10.1016/0272-0590(89)90033-x.
Epidemiological studies have implicated nitroso compounds as possible causative agents for human childhood cancers, including those of neurogenic origin. Published evidence from animal models, which is reviewed in this report, indicates that capacity for metabolic activation of nitrosamines is limited in rodent fetuses and that nitrosamines are correspondingly weak transplacental carcinogens. The C3H mouse fetus, however, has both moderate capability for activation of N-nitrosodimethylamine (NDMA) and proven susceptibility to transplacental causation of neurogenic tumors by a nitrosourea. We tested whether NDMA could act as a transplacental carcinogen in the C3H mouse, and whether it or N-nitrosodiethylamine (NDEA) would initiate neurogenic tumors. N-Nitrosoethylurea (NEU) served as positive control. C3H/HeNCr MTV- pregnant mice were treated ip on Gestation Day 16 or 19 with NDMA (0.1 mmol, 7.4 mg/kg, maximum nonfetotoxic dose), NDEA (0.5 mmol, 51 mg/kg), or NEU (0.4 mmol, 47 mg/kg). NDMA had significant transplacental carcinogenic effects, resulting in an increase in percentage female offspring with hepatocellular carcinomas and in average number of liver tumors after treatment on either gestational day, compared with controls. In the males there was a significant increase in numbers of liver tumors and carcinomas following Day 19 exposure. An increase in incidence of histiocytic and undifferentiated sarcomas was also of statistical significance. There was no change in number of pulmonary tumors. One intracranial schwannoma resulted. NDEA had no effect when given on Gestation Day 16, but caused a significant increase in liver and lung tumor numbers in both sexes when treatment was on Day 19. NEU induced the expected high incidence of lung tumors, significantly increased liver tumor incidence in females (Day 19 exposure), and produced schwannomas in 14 and 35% of the offspring after Days 16 or 19 treatment, respectively. The results show that NDMA at even a low dose had significant transplacental carcinogenic effects, including one schwannoma, which was most unlikely to have occurred spontaneously. However, this single neurogenic tumor contrasts with the absence of similar neoplasms in mice exposed transplacentally to NDEA, in view of the generally greater efficiency of ethylating agents as carcinogens for the nervous system in rodents. These data thus neither conclusively support nor refute the hypothesis that nitrosamines may initiate neurogenic tumors in fetuses.
流行病学研究表明，亚硝基化合物可能是人类儿童癌症（包括神经源性癌症）的致病因素。本报告中回顾的动物模型的已发表证据表明，啮齿动物胎儿中亚硝胺的代谢活化能力有限，因此亚硝胺是相对较弱的经胎盘致癌物。然而，C3H小鼠胎儿具有中等程度的N-亚硝基二甲胺（NDMA）活化能力，并且已证实对亚硝基脲经胎盘诱发神经源性肿瘤敏感。我们测试了NDMA是否能在C3H小鼠中作为经胎盘致癌物，以及它或N-亚硝基二乙胺（NDEA）是否会引发神经源性肿瘤。N-亚硝基乙基脲（NEU）用作阳性对照。在妊娠第16天或第19天，对C3H/HeNCr MTV-怀孕小鼠腹腔注射NDMA（0.1 mmol，7.4 mg/kg，最大非胚胎毒性剂量）、NDEA（0.5 mmol，51 mg/kg）或NEU（0.4 mmol，47 mg/kg）。NDMA具有显著的经胎盘致癌作用，与对照组相比，在任何一个妊娠日进行处理后，雌性后代肝细胞癌的百分比以及肝脏肿瘤的平均数量均增加。在雄性中，第19天暴露后肝脏肿瘤和癌的数量显著增加。组织细胞性和未分化肉瘤的发生率增加也具有统计学意义。肺部肿瘤数量没有变化。出现了一例颅内神经鞘瘤。在妊娠第16天给予NDEA没有影响，但在第19天进行处理时，两性的肝脏和肺部肿瘤数量均显著增加。NEU诱导出预期的高发性肺部肿瘤，雌性（第19天暴露）的肝脏肿瘤发生率显著增加，在第16天或第19天处理后，分别有14%和35%的后代产生神经鞘瘤。结果表明，即使是低剂量的NDMA也具有显著的经胎盘致癌作用，包括一例神经鞘瘤，其极不可能自发发生。然而，鉴于乙基化剂作为啮齿动物神经系统致癌物的效率通常更高，这单个神经源性肿瘤与经胎盘暴露于NDEA的小鼠中缺乏类似肿瘤形成对比。因此，这些数据既没有确凿支持也没有反驳亚硝胺可能引发胎儿神经源性肿瘤这一假说。
