Miller M S, Jones A B, Chauhan D P, Anderson L M
Perinatal Carcinogenesis Section, National Cancer Institute, Frederick Cancer Research and Development Center, MD 21702.
Carcinogenesis. 1990 Nov;11(11):1979-84. doi: 10.1093/carcin/11.11.1979.
Treatment of pregnant mice with 3-methylcholanthrene (MC) causes lung and liver tumors in the offspring, the incidences of which are greatly influenced by the Ah locus regulated induction phenotype for aryl hydrocarbon hydroxylase activity (AHH) in both the mother and fetuses. In order to examine the biochemical and molecular mechanisms responsible for the modulating effect of maternal environment on tumor susceptibility, reciprocal crosses between responsive C57BL/6 and non-responsive DBA/2 mice were made and the pregnant mothers were treated i.p. on the 17th day of gestation with either olive oil alone, 30 mg/kg of MC, or 30 mg/kg of beta-naphthoflavone (beta NF). At various times after injection, the mothers were killed and the fetuses removed for enzymatic and molecular blot analysis. In fetal lung tissues, the absolute levels and relative induction ratios of AHH activity from D2B6F1 fetuses were very similar to those obtained in B6D2F1 fetuses during the first 24 h following a transplacental exposure to either inducing agent. This was also the case 48 h after an injection of beta NF. However, 48 h after exposure to MC, the AHH activity in fetal lungs from B6 mothers had declined to practically control values, whereas fetal lungs from D2 mothers still exhibited a high level of AHH activity. Similar induction kinetics for the CYPIA1 gene were obtained in fetal livers. These results were confirmed at the RNA level by quantitative slot-blot analysis of fetal RNA preparations. In both organs, treatment with inducing agents for the P450IA1 gene resulted in a rapid and early induction of CYPIA1 RNA by 4 h. Fetuses from D2 mothers, however, showed a more sustained induction of CYPIA1 RNA following exposure to MC than did fetuses from B6 mothers. These results suggest that the observed increase in tumor susceptibility observed in the offspring of D2 mothers compared to the offspring of B6 mothers was due, at least in part, to the differences in the persistence of induction of the CYPIA1 gene locus, and may be the result of differences in the clearance rates of MC from the fetal and maternal compartments or its pharmacokinetic distribution in the two types of maternal environments.
用3 - 甲基胆蒽（MC）处理怀孕小鼠会导致其后代出现肺和肝肿瘤，肿瘤的发生率受母鼠和胎儿中芳烃羟化酶活性（AHH）的Ah位点调控诱导表型的显著影响。为了研究母体环境对肿瘤易感性调节作用的生化和分子机制，进行了反应性C57BL/6小鼠和无反应性DBA/小鼠之间的正反交实验，并在妊娠第17天给怀孕的母鼠腹腔注射单独的橄榄油、30mg/kg的MC或30mg/kg的β - 萘黄酮（β - NF）。在注射后的不同时间，处死母鼠并取出胎儿进行酶学和分子印迹分析。在胎儿肺组织中，D2B6F1胎儿的AHH活性的绝对水平和相对诱导率与经胎盘暴露于任何一种诱导剂后的前24小时内在B6D2F1胎儿中获得的结果非常相似。注射β - NF后48小时也是如此。然而，暴露于MC后48小时，来自B6母鼠的胎儿肺中的AHH活性已下降至几乎接近对照值，而来自D2母鼠的胎儿肺仍表现出高水平的AHH活性。在胎儿肝脏中获得了类似的CYP1A1基因诱导动力学。通过对胎儿RNA制剂的定量狭缝印迹分析在RNA水平证实了这些结果。在这两个器官中，用P450IA1基因的诱导剂处理导致CYP1A1 RNA在4小时时迅速且早期诱导。然而，与来自B6母鼠的胎儿相比，来自D2母鼠的胎儿在暴露于MC后显示出对CYP1A1 RNA更持久的诱导。这些结果表明，与B6母鼠的后代相比，在D2母鼠的后代中观察到的肿瘤易感性增加至少部分是由于CYP1A1基因位点诱导持续性的差异，并且可能是MC从胎儿和母体区室清除率的差异或其在两种母体环境中的药代动力学分布差异的结果。
