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Published on: April 26, 2018
Acrylamide induces specific DNA adduct formation and gene mutations in a carcinogenic target site, the mouse lung
Yuji Ishii1, Kohei Matsushita1, Ken Kuroda1
1Division of Pathology and Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Abstract:
Acrylamide (AA) is a contaminant in heated foods and is carcinogenic in multiple organs of rodents. There have been many reports regarding AA-induced DNA modification and genotoxicity. However, the data are insufficient to understand fully the relationship between the two events. A recent report demonstrated carcinogenicity in the mouse lung. The lung is advantageous for investigation of AA-induced genotoxicity because DNA adduct levels are relatively high in this organ. In the present study, reporter gene mutation assays and quantitative analyses of specific DNA adducts were performed in the lungs of mature gpt delta mice treated with AA at doses of 100, 200 and 400 p.p.m. in drinking water for 4 weeks. N7-GA-Gua was detected in all AA-treated mice in a dose-dependent manner. gpt mutant frequencies (MFs) were significantly increased in the middle- and high-dose groups. In the analysis of mutation spectra, significant increases in GC-TA transversions and single base deletion mutations were observed in the high-dose group. Spi(-) MFs were significantly increased in the high-dose group. Analysis of Spi(-) mutants revealed significant increases in the frequencies of single base deletion mutation in runs of G/C and A/T. Analyses of immature mice under the same experimental conditions showed that there were no differences of susceptibility to AA-induced genotoxicity in the two age classes. The overall data clearly show the causal relationship between AA-induced DNA adducts and the gene mutations at carcinogenic target sites.
Insights
Acrylamide (AA) exposure in mice causes DNA damage and gene mutations in the lungs, confirming a link between adducts and genotoxicity. This study clarifies AA
Area of Science:
- Toxicology
- Genetics
- Carcinogenesis
Background:
- Acrylamide (AA) is a food contaminant and rodent carcinogen.
- AA-induced DNA modification and genotoxicity are reported, but their relationship needs clarification.
- The mouse lung is suitable for studying AA genotoxicity due to high DNA adduct levels.
Purpose of the Study:
- To investigate the relationship between acrylamide-induced DNA adducts and gene mutations in mouse lungs.
- To quantify DNA adducts and mutation frequencies following AA exposure.
- To analyze mutation spectra and assess age-related susceptibility to AA genotoxicity.
Main Methods:
- Mature gpt delta mice were exposed to AA (100, 200, 400 p.p.m.) in drinking water for 4 weeks.
- Reporter gene mutation assays and quantitative analyses of N7-GA-Gua DNA adducts were performed.
- Mutation spectra and Spi(-) mutant frequencies were analyzed.
Main Results:
- N7-GA-Gua adducts increased dose-dependently in AA-treated mice.
- GPT mutant frequencies significantly elevated in middle- and high-dose groups.
- GC-TA transversions and single base deletions observed in high-dose group mutation spectra.
- Spi(-) mutant frequencies and single base deletions in G/C and A/T runs increased significantly.
- No significant age-related differences in susceptibility to AA genotoxicity were found.
Conclusions:
- AA exposure causes dose-dependent DNA adduct formation and gene mutations in mouse lungs.
- The study establishes a causal relationship between AA-induced DNA adducts and genotoxicity at carcinogenic sites.
- Findings support the role of AA in lung genotoxicity and potential carcinogenicity.
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