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Persistence of methylated purines in the dna of various rat fetal and maternal tissues and carcinogenesis in the offspring following a single transplacental dose of N ‐methyl‐ N ‐nitrosourea
Author(s) -
Likhachev A. J.,
Alexandrov V. A.,
Anisimov V. N.,
Bespalov V. G.,
Korsakov M. V.,
Ovsyannikov A. I.,
Popovic I. G.,
Napalkov N. P.,
Tomatis L.
Publication year - 1983
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910310618
Subject(s) - offspring , transplacental , persistence (discontinuity) , carcinogenesis , fetus , purine metabolism , biology , dna , nitrosourea , genetics , carcinogen , microbiology and biotechnology , physiology , medicine , pregnancy , biochemistry , gene , placenta , chemotherapy , enzyme , geotechnical engineering , engineering
Formation and loss of methylated purines in DNA of various fetal and maternal tissues were measured up to 7 days following intravenous administration of N ‐[ 14 C]methyl‐ N ‐nitrosourea to rats on the 21st day of gestation. Methylation products were detected in all tissues examined, the level in maternal liver being higher than in other tissues. The concentrations of 7‐methylguanine and 3‐methyladenine decreased faster in fetal than in corresponding maternal tissues, due to a higher rate of DNA synthesis in fetal tissues, as determined by incorporation of labelled thymidine. Removal of the promutagenic DNA lesion O 6 ‐methylguanine was most efficient in maternal and fetal liver; but it was very poorly repaired in kidney and brain. The persistence of O 6 ‐methylguanine relative to 7‐methylguanine was highest in the DNA of fetal brain. The principal targets for the transpacental carcinogenic effect of N ‐methyl‐ N ‐nitrosourea under these experimental conditions were fetal neurogenic tissue and kidney; and malignant tumors developed at these sites in 31‐34% and 15‐16% of male and female descendants, respectively. These results support the concept that a complex interaction between DNA alkylation, repair and replication is the molecular basis of initiation of carcinogenesis by alkylating agents.