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

Abstract

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-[14C]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 O6-methylguanine was most efficient in maternal and fetal liver; but it was very poorly repaired in kidney and brain. The persistence of O6-methylguanine relative to 7-methylguanine was highest in the DNA of fetal brain. The principal targets for the transplacental 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.

Environmental Neurotoxins Linked to a Prototypical Neurodegenerative Disease

“…The brains of young adult Mgmt −/− mice treated with a single systemic dose of MAM showed significantly higher levels of O 6 -mG than the brains of comparably treated C57BL/6 wild-type mice. These data are consistent with the established developmental, neurotoxic, and carcinogenic properties of MAM in rodents [151][152][153][154]. The O 6 -mG levels were linked to changes in the expression of genes in several cell-signaling pathways (i.e., tumor protein p53 [TP53], nuclear factor κB [NFκB], mitogen-activated protein kinase [MAPK]) associated with cancer, human neurological disease, and neurodevelopmental and skin disorders.…”

Placental Oxidative Stress Alters Expression of Murine Osteogenic Genes and Impairs Fetal Skeletal Formation

“…Additionally, MNU may also directly alter fetal growth by traversing placental barriers, damaging fetal DNA damage (formation of adducts, point mutations, etc. ), or causing protein nitration via increased peroxynitrite production [35]. Future studies will include evaluation of MNU and OS in fetal tissues, and their ability to directly influence appendicular growth.…”

Critical Windows of Exposure for Children's Health: Cancer in Human Epidemiological Studies and Neoplasms in Experimental Animal Models

“…The repair capacity for 06-methylguanine was also very poor in fetal rat kidney compared to liver (168). Also in rats, DNA are not seen after transplacental exposure of mice, which establish a fully differentiated kidney by GD 17-18, or of hamsters, which have a functional kidney by GD 13.…”

“…06-alkylguanine is a major promutagenic adduct resulting from the reaction of ENU or methylnitrosourea (MNU) with DNA. Repair of this lesion by 06-alkylguanine-DNA alkyltransferase occurs at a considerably slower rate in the fetal rat brain, the target organ, than in other tissues (166)(167)(168). The level of the enzyme is maximum on GD 12, and decreases thereafter (169).…”