32P-postlabeling assay in mice of transplacental DNA damage induced by the environmental carcinogens safrole, 4-aminobiphenyl, and benzo(a)pyrene.
32P-postlabeling assay in mice of transplacental DNA damage induced by the environmental carcinogens safrole, 4-aminobiphenyl, and benzo(a)pyrene.
复制标题
DOI：
--
复制
发表时间：
1986-06
期刊：
影响因子：
11.2
通讯作者：
L. Lu;R. M. Disher;M. Reddy;K. Randerath
中科院分区：
文献类型：
--
作者：
L. Lu;R. M. Disher;M. Reddy;K. Randerath
已知胎儿经胎盘暴露于致癌物会诱发后代肿瘤，通常发病率高且潜伏期短。虽然DNA的共价加合似乎是肿瘤发生所必需的，但对致癌物与胎儿组织DNA的结合知之甚少。一种灵敏的32 P后标记方法使我们能够研究环境致癌物黄樟素（600 μ mol/kg p.o.），4-氨基联苯（800 μ mol/kg）和苯并（a）芘（200 μ mol/kg）对妊娠ICR小鼠在妊娠第18天给予试验致癌物后各种母体和胎儿组织DNA的影响。结果表明，这些致癌物与母胎肝、肺、肾、心、脑、肠、皮肤、母体子宫和胎盘的DNA结合，并存在器官特异性的定量和定性差异。这是第一次有可能分析微量组织中的DNA加合物模式，例如可从胎儿心脏获得的那些。黄樟素处理后24小时，估计不同器官的共价结合指数（μ mol加合核苷酸/mol DNA核苷酸/μ mol致癌物/g体重），母体和胎儿DNA的范围分别为0.1至247和0.1至5.8。共价结合指数值分别为0.2至13和0.1至0.3的母亲和胎儿的DNA，发现4-氨基联苯。苯并（a）芘处理产生的共价结合指数值分别为0.6至6.5和0.3至0.7的母亲和胎儿的DNA。在母体和胎儿组织中，黄樟素表现出优先结合肝脏DNA。4-氨基联苯优先结合母体肝脏和肾脏的DNA，但在胎儿组织中没有表现出偏好。苯并（a）芘在母体和胎儿器官中均表现出较弱的组织偏好性。对于所有研究的化合物，胎儿加合物水平通常低于相应的母体加合物水平，特别是当母体内收水平高时。主要的发现是，几种不同结构的致癌物或其代谢产物很容易穿过胎盘，并在胎儿器官中产生DNA加合物。在快速增殖的组织中所产生的DNA损伤可能在经胎盘癌变中起关键作用。
Transplacental exposure of fetuses to carcinogens is known to induce tumors in the offspring, often with a high incidence and short latency. While covalent adduction of DNA appears to be essential for tumor initiation, little is known about the binding of carcinogens to the DNA of fetal tissues. A sensitive 32P-postlabeling method enabled us to study the binding of the environmental carcinogens safrole (600 mumol/kg p.o.), 4-aminobiphenyl (800 mumol/kg), and benzo(a)pyrene (200 mumol/kg) to the DNA of various maternal and fetal tissues after administration of test carcinogens to pregnant ICR mice on day 18 of gestation. The results show that these carcinogens bound to the DNA of maternal and fetal liver, lung, kidney, heart, brain, intestine, skin, maternal uterus, and placenta, with organ-specific quantitative and qualitative differences. It was possible for the first time to analyze DNA adduct patterns in minute amounts of tissue, for example those available from fetal heart. The covalent binding index (mumol adducted nucleotides per mol of DNA nucleotides/mumol carcinogen administered per g body weight) 24 h after safrole treatment was estimated for the different organs and ranged from 0.1 to 247 and 0.1 to 5.8 for maternal and fetal DNA, respectively. Covalent binding index values of 0.2 to 13 and 0.1 to 0.3 for maternal and fetal DNA, respectively, were found for 4-aminobiphenyl. Benzo(a)pyrene treatment yielded covalent binding index values of 0.6 to 6.5 and 0.3 to 0.7 for maternal and fetal DNA, respectively. In both maternal and fetal tissues, safrole exhibited preferential binding to liver DNA. 4-Aminobiphenyl bound preferentially to DNA of maternal liver and kidney but showed no preference among fetal tissues. Benzo(a)pyrene exhibited weak tissue preference in both maternal and fetal organs. For all of the compounds studied, the fetal adduct levels were generally lower than the corresponding maternal adduct levels, especially when the level of maternal adduction was high. The major finding was that several carcinogens of diverse structure or their metabolites readily crossed the placenta and gave rise to DNA adducts in fetal organs. The resulting DNA damage in rapidly proliferating tissues may play a critical role in transplacental carcinogenesis.