DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine

Abstract

Groups of lambda lacZ transgenic mice were treated i.p. with N-nitrosodimethylamine (NDMA) as single doses of 5 mg/kg or 10 mg/kg or as 10 daily doses of 1 mg/kg and changes in DNA N7- or O6-methylguanine or the repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) were followed for up to 14 days in various tissues. Adduct induction in the liver exceeded by at least one order of magnitude than observed in the next nearest target tissue (lung), and was approximately linearly related to dose, except for O6-methylguanine after the first dose of 1 mg/kg which was lower than expected. Substantial induction of lambda lacZ mutagenesis was observed only in the liver, where the mutant frequency was already maximal within 7 days after 5 mg/kg NDMA and remained unchanged thereafter up to 49 days. Small but marginally significant increases in mutant frequency were consistently observed in the spleen after all three modes of treatment. A lack of proportionality between mutation induction and the administered dose or the corresponding adduct levels was observed, probably reflecting the importance of toxicity-related cell proliferation caused by NDMA at higher doses. Twenty eight days after a dose of 10 mg/kg (causing a 3.6-fold increase in mutant frequency), NDMA was found to increase the frequency of GC-->AT mutations (with a concomitant shift of their preferential location from CpG sites to GpG sites), which made up approximately 60% of the induced mutations. Surprisingly, NDMA also caused a significant increase in deletions of a few (up to 11) base-pairs (22%).

Hepatocarcinogenesis Driven by GSNOR Deficiency Is Prevented by iNOS Inhibition

“…While AGT decrease after nitrosamine treatment largely recovers by day 4 in wild-type mice (36), AGT level remains low in GSNOR −/− mice 4 to 6 days after DEN challenge (24). Therefore, we treated the DEN-challenged GSNOR −/− mice with 1400W twice a day for 4 days (Fig.…”

Sequencing Chemically Induced Mutations in the Mutamouse Lacz Reporter Gene Identifies Human Cancer Mutational Signatures

“…About 50% of the NDMA mutation profile was explained by the SBS 30 signature that has been associated with a deficiency in base excision repair. NDMA is known to induce mostly 0 6 - and N 7 -methyl guanine adducts 34 , thus, a role of base excision repair in the response to this chemical is expected. NDMA exposure was also enriched for SBS 11 (37%), inducing primarily C>T mutations at C pC motifs (Supplementary Figure S4).…”

“…To further compare lacZ mutation spectra and COSMIC signatures, published Sanger sequencing data from 17 studies involving eight mutagens were also examined (Supplementary Table S1). These studies include data from mice exposed to electromagnetic radiation 29,30,31,32,33 , alkylating agents and adduct-forming agents 34,35,36,37,38,39,40 , and a nitrogenous base analog 41 . Data from control animals in these studies and others 42,43,44,45,46 were also included to generate a background mutation signature.…”

Genotoxic effects of N-nitrosodimethylamine in somatic and generative cells of mice

“…Одна ко ис-следования in vivo на млекопитающих немногочисленны и носят противоречивый характер [20][21][22][23]. Практически не изучено влияние НДМА на половые клетки и репро-дуктивный потенциал животных.…”