Donovan P J
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
Mutat Res. 1999 Jun 1;427(1):59-63. doi: 10.1016/S0027-5107(99)00086-X.
In a clear demonstration of the changing sensitivity of the developing mammal to transplacental carcinogenesis, Ivankovic and Druckrey [S. Ivankovic, H. Druckrey, Transplacentare Erzeugung maligner Tumoren des Nervensystem: I. Athyl-nitroso-harnstoff (ANH) an BD IX-Ratten, Z. Krebsforsch. 71 (1968) 320-360] exposed pregnant BD IX rats to a pulse of N-ethyl-N-nitrosourea (ENU), a reactive carcinogen with a half-life of 20 min. No tumors were seen with ENU exposure before gestation day 12, but the multiplicity of neurogenic tumors increased steadily thereafter and was greatest with treatment on day 20, followed by a decline in sensitivity for the last three days of gestation. Similarly, a transplacental study of ENU in the Syrian hamster [B.A. Diwan, S. Rehm, J.M. Rice, Age- and dose-dependent transplacental carcinogenesis by N-nitrosoethylurea in Syrian golden hamsters, J. Cancer Res. Clin. Oncol. 122 (1996) 643-652] found that the numbers of tumors induced were greatest after exposure of late fetal stages. While these observations suggested that embryonic cells are refractory to carcinogenesis, an alternative explanation could be that a significant tumor yield was not observed because too few target cells were present in the embryo. I have resolved this issue by combining these published data with others on the numbers of neuroectodermal cells in the developing BD IX rat brain [R. Müller, M.F. Rajewsky, Elimination of O6-ethylguanine from the DNA of brain, liver, and other rat tissues exposed to ethylnitrosourea at different stages of prenatal development, Cancer Res. 43 (1983) 2897-2904] and total cell counts of successive developmental stages of the Syrian hamster fetus [P.J. Donovan, G.T. Smith, Cell sensitivity to transplacental mutagenesis by N-ethyl-N-nitrosourea is greatest during early gestation in the Syrian hamster, Mutation Res., 1999, this issue], allowing the risk per cell at different stages of gestation to be calculated. Sensitivity to carcinogenesis was found to be greatest early in gestation and to decrease as gestation proceeds. For the rat model, tumor frequency per cell changed from 1.3x10(-6) at day 12 exposure to 2.6x10(-8) at day 23 exposure, a 50-fold decrease. For the hamster model, the tumor-initiation rate decreased 1250-fold from 1.2x10(-5) at day 7 exposure to 9.6x10(-9) at day 13 exposure. Thus, two independent experiments with different rodent species demonstrate that sensitivity of individual cells to damage leading to transplacental carcinogenesis is greatest in the early fetus and lessens markedly as gestation proceeds, in parallel with changing sensitivity to mutation (Donovan et al., Mutat. Res., this issue).
伊万科维奇和德鲁克雷 [S. 伊万科维奇，H. 德鲁克雷，《经胎盘诱发神经系统恶性肿瘤：I. N - 乙基 - N - 亚硝基脲（ENU）对BD IX品系大鼠的作用》，《癌症研究杂志》71 (1968) 320 - 360] 通过让怀孕的BD IX品系大鼠接触一次N - 乙基 - N - 亚硝基脲（ENU，一种半衰期为20分钟的反应性致癌物），清楚地证明了发育中的哺乳动物对经胎盘致癌作用的敏感性变化。在妊娠第12天之前接触ENU未观察到肿瘤，但此后神经源性肿瘤的数量稳步增加，在第20天进行处理时数量最多，随后在妊娠的最后三天敏感性下降。同样，一项关于ENU对叙利亚仓鼠经胎盘作用的研究 [B.A. 迪万，S. 雷姆，J.M. 赖斯，《N - 亚硝基乙基脲在叙利亚金仓鼠中经胎盘致癌作用的年龄和剂量依赖性》，《癌症研究与临床肿瘤学杂志》122 (1996) 643 - 652] 发现，在胎儿后期接触后诱发的肿瘤数量最多。虽然这些观察结果表明胚胎细胞对致癌作用具有抗性，但另一种解释可能是未观察到显著的肿瘤产量是因为胚胎中存在的靶细胞太少。我通过将这些已发表的数据与关于发育中的BD IX品系大鼠脑中神经外胚层细胞数量的其他数据 [R. 米勒，M.F. 拉耶夫斯基，《在产前发育不同阶段暴露于乙基亚硝基脲的大鼠脑、肝及其他组织DNA中O6 - 乙基鸟嘌呤的消除》，《癌症研究》43 (1983) 2897 - 2904] 以及叙利亚仓鼠胎儿连续发育阶段的总细胞计数 [P.J. 多诺万，G.T. 史密斯，《叙利亚仓鼠在妊娠早期对N - 乙基 - N - 亚硝基脲经胎盘诱变的细胞敏感性最高》（《突变研究》，1999年，本期）] 相结合，解决了这个问题，从而能够计算妊娠不同阶段每个细胞的风险。发现对致癌作用的敏感性在妊娠早期最高，并随着妊娠的进行而降低。对于大鼠模型，每个细胞的肿瘤发生率从第12天接触时的1.3×10⁻⁶ 变为第23天接触时的2.6×10⁻⁸，下降了50倍。对于仓鼠模型，肿瘤起始率从第7天接触时的1.2×10⁻⁵ 下降到第13天接触时的9.6×10⁻⁹，下降了1250倍。因此，两项使用不同啮齿动物物种的独立实验表明，单个细胞对导致经胎盘致癌作用的损伤的敏感性在胎儿早期最高，并随着妊娠的进行而显著降低，这与对突变的敏感性变化情况一致（多诺万等人，《突变研究》，本期）。
