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Oxidative-stress-driven mutagenesis in the small intestine of the gpt delta mouse induced by oral administration of potassium bromate.
- Source :
-
Mutation research. Genetic toxicology and environmental mutagenesis [Mutat Res Genet Toxicol Environ Mutagen] 2020 Feb - Mar; Vol. 850-851, pp. 503136. Date of Electronic Publication: 2020 Jan 15. - Publication Year :
- 2020
-
Abstract
- Tumorigenesis induced by oxidative stress is thought to be initiated by mutagenesis, but via an indirect mechanism. The dose-response curves for agents that act by this route usually show a threshold, for unknown reasons. To gain insight into these phenomena, we have analyzed the dose response for mutagenesis induced by the oral administration of potassium bromate, a typical oxidative-stress-generating agent, to gpt delta mice. The agent was given orally for 90 d to either Nrf2+ or Nrf2-knockout (KO) mice and mutants induced in the small intestine were analyzed. In Nrf2+mice, the mutant frequency was significantly greater than in the vehicle controls at a dose of 0.6 g/L but not at 0.2 g/L, indicating that a practical threshold for mutagenesis lies between these doses. At 0.6 g/L, the frequencies of G-to-T transversions (landmark mutations for oxidative stress) and G-to-A transitions were significantly elevated. In Nrf2-KO mice, too, the total mutant frequency was increased only at 0.6 g/L. G-to-T transversions are likely to have driven tumorigenesis in the small intestine. A site-specific G-to-T transversion at guanine (nucleotide 406) in a 5'-TGAA-3' sequence in gpt, and our primer extension reaction showed that formation of the oxidative DNA base modification 8-oxo-deoxyguanosine (8-oxo-dG) at nucleotide 406 was significantly increased at doses of 0.6 and 2 g/L in the gpt delta mice. In the Apc oncogene, guanine residues in the same or similar sequences (TGAA or AGAA) are highly substituted by thymine (G-to-T transversions) in potassium bromate-induced tumors. We propose that formation of 8-oxo-dG in the T(A)GAA sequence is an initiating event in tumor formation in the small intestine in response to oxidative stress.<br />Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest.<br /> (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Subjects :
- 8-Hydroxy-2'-Deoxyguanosine genetics
Administration, Oral
Animals
Bromates pharmacology
Carcinogenesis drug effects
Carcinogenesis genetics
DNA drug effects
DNA genetics
Dose-Response Relationship, Drug
Intestine, Small drug effects
Intestine, Small pathology
Mice
Mice, Knockout
Mutagenesis drug effects
Mutation
NF-E2-Related Factor 2 genetics
Oxidative Stress drug effects
Bromates toxicity
Mutagenesis genetics
Oxidative Stress genetics
Pentosyltransferases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3592
- Volume :
- 850-851
- Database :
- MEDLINE
- Journal :
- Mutation research. Genetic toxicology and environmental mutagenesis
- Publication Type :
- Academic Journal
- Accession number :
- 32247553
- Full Text :
- https://doi.org/10.1016/j.mrgentox.2020.503136