DNA of various maternal and fetal tissues after administration of test

Transplacental exposureof fetusesto carcinogensis kno@i to induce tumors in the offspring, often with a high incidenceand 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 sensitive32P-postlabelingmethod enabled us to study the binding of the environmental carcinogens safrole (600 Mmol/kg p.o.), 4aminobiphenyl (800 @imol/kg), and benzo(a)pyrene (200 ,anol/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-specificquantitative and qualitative differences. It waspossiblefor the first timeto analyzeDNA adductpatternsin minute amounts of tissue, for example those available from fetal heart. The covalent binding index (imol adducted nucleotides per mol of DNA nucleotides/@imol carcinogenadministered 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 maternaland 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 ofO.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-Aminobiphenylbound 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 thecompoundstudied,thefetaladductlevelsweregenerallylower than the corresponding maternal adduct levels, especially when the level of maternaladductionwas high. The major finding was that several carcinogensof 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.