32P-postlabeling assay in mice of transplacental DNA damage induced by the environmental carcinogens safrole, 4-aminobiphenyl, and benzo(a)pyrene.
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.
L J
LJ
Lu
R M
RM
Disher
M V
MV
Reddy
K
K
Randerath
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D000611:Aminobiphenyl Compounds / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D001580:Benzopyrenes / Q000378:metabolism; D001711:Biotransformation; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts; D004149:Dioxoles / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008813:Mice, Inbred ICR; D010761:Phosphorus Radioisotopes; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D012451:Safrole / Q000378:metabolism / Q000633:toxicity*
D000611:Aminobiphenyl Compounds; D001580:Benzopyrenes; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D004149:Dioxoles; D010761:Phosphorus Radioisotopes; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; C006757:4-biphenylamine; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D004247:DNA; D012451:Safrole