Induction of micronuclei in mouse and rat by glycidamide, genotoxic metabolite of acrylamide

Paulsson, Birgit; Kotova, Natalia; Grawé, Jan; Henderson, Alex; Granath, Fredrik; Golding, Bernard T.; Törnqvist, Margareta

doi:10.1016/s1383-5718(02)00281-4

Cited by 101 publications

(50 citation statements)

References 24 publications

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“…Our previous study on the DNA adducts produced by AA and GA in mice indicated that significantly higher levels of N7-dG-GA and N3-dA-GA DNA adducts are formed in the liver and lungs of male mice than female mice [Gamboa da Costa et al, 2003]. Previous studies indicate that AA and GA induce micronuclei in rodents [Paulsson et al, 2002[Paulsson et al, , 2003. In this study, we also examined the peripheral blood from mice exposed to the high doses of AA and GA for MNRETs.…”

Section: Discussionmentioning

confidence: 99%

Genotoxicity of acrylamide and its metabolite glycidamide administered in drinking water to male and female Big Blue mice

Manjanatha

Aidoo

Shelton

et al. 2005

Environ and Mol Mutagen

100

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The recent discovery of acrylamide (AA), a probable human carcinogen, in a variety of fried and baked starchy foods has drawn attention to its genotoxicity and carcinogenicity. Evidence suggests that glycidamide (GA), the epoxide metabolite of AA, is responsible for the genotoxic effects of AA. To investigate the in vivo genotoxicity of AA, groups of male and female Big Blue (BB) mice were administered 0, 100, or 500 mg/l of AA or equimolar doses of GA, in drinking water, for 3-4 weeks. Micronucleated reticulocytes (MN-RETs) were assessed in peripheral blood within 24 hr of the last treatment, and lymphocyte Hprt and liver cII mutagenesis assays were conducted 21 days following the last treatment. Further, the types of cII mutations induced by AA and GA in the liver were determined by sequence analysis. The frequency of MN-RETs was increased 1.7-3.3-fold in males treated with the high doses of AA and GA (P < or = 0.05; control frequency = 0.28%). Both doses of AA and GA produced increased lymphocyte Hprt mutant frequencies (MFs), with the high doses producing responses 16-25-fold higher than that of the respective control (P < or = 0.01; control MFs = 1.5 +/- 0.3 x 10(-6) and 2.2 +/- 0.5 x 10(-6) in females and males, respectively). Also, the high doses of AA and GA produced significant 2-2.5-fold increases in liver cII MFs (P < or = 0.05; control MFs = 26.5 +/- 3.1 x 10(-6) and 28.4 +/- 4.5 x 10(-6)). Molecular analysis of the mutants indicated that AA and GA produced similar mutation spectra and that these spectra were significantly different from that of control mutants (P < or = 0.001). The predominant types of mutations in the liver cII gene from AA- and GA-treated mice were G:C-->T:A transversions and -1/+1 frameshifts in a homopolymeric run of Gs. The results indicate that both AA and GA are genotoxic in mice. The MFs and types of mutations induced by AA and GA in the liver are consistent with AA exerting its genotoxicity in BB mice via metabolism to GA.

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Section: Discussionmentioning

confidence: 99%

Genotoxicity of acrylamide and its metabolite glycidamide administered in drinking water to male and female Big Blue mice

Manjanatha

Aidoo

Shelton

et al. 2005

Environ and Mol Mutagen

100

View full text Add to dashboard Cite

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“…The genotoxicity of AA has been studied extensively, but there are fewer experimental data available with GA as the test substance (Baum et al, 2005;Besaratinia and Pfeifer, 2004;Koyama et al, 2006;Martins et al, 2006;Paulsson et al, 2003). AA is not mutagenic in bacterial assays, and it is mutagenic in mammalian somatic and germinal cells in vitro and in vivo (Dearfield et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

Mei

Churchwell

et al. 2008

Food and Chemical Toxicology

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In addition to occupational exposures to acrylamide (AA), concerns about AA health risks for the general population have been recently raised due to the finding of AA in food. In this study, we evaluated the genotoxicity of AA and its metabolite glycidamide (GA) in L5178Y/ Tk +/− mouse lymphoma cells. The cells were treated with 2-18 mM of AA or 0.125-4 mM of GA for 4 h without metabolic activation. The DNA adducts, mutant frequencies and the types of mutations for the treated cells were examined. Within the dose range tested, GA induced DNA adducts of adenine and guanine [N3-(2-carbamoyl-2-hydroxyethyl)-adenine and N7-(2-carbamoyl-2-hydroxyethyl)-guanine] in a linear dose-dependent manner. The levels of guanine adducts were consistently about 60-fold higher across the dose range than those of adenine. In contrast, no GAderived DNA adducts were found in the cells treated with any concentrations of AA, consistent with a lack of metabolic conversion of AA to GA. However, the mutant frequency was significantly increased by AA at concentrations of 12 mM and higher. GA was mutagenic starting with the 2 mM dose, suggesting that GA is much more mutagenic than AA. The mutant frequencies were increased with increasing concentrations of AA and GA, mainly due to an increase of proportion of small colony mutants. To elucidate the underlying mutagenic mechanism, we examined the loss of heterozygosity (LOH) at four microsatellite loci spanning the entire chromosome 11 for mutants induced by AA or GA. Compared to GA induced mutations, AA induced more mutants whose LOH extended to D11Mit22 and D11Mit74, an alteration of DNA larger than half of the chromosome. Statistical analysis of the mutational spectra revealed a significant difference between the types of mutations induced by AA and GA treatments (P = 0.018). These results suggest that although both AA and GA generate mutations through a clastogenic mode of action in mouse lymphoma cells, GA induces mutations via a DNA adduct mechanism whereas AA induces mutations by a mechanism not involving the formation of GA adducts.

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“…This fact, together with the genotoxicity of GA, has led to the assumption that GA is the genotoxic agent and probably also the cancer-risk increasing factor in AA exposure (e.g. [10]). …”

Section: Introductionmentioning

confidence: 99%

Differences in hemoglobin adduct levels of acrylamide in the general population with respect to dietary intake, smoking habits and gender

Hagmar

Wirfält

Paulsson

et al. 2005

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Induction of micronuclei in mouse and rat by glycidamide, genotoxic metabolite of acrylamide

Cited by 101 publications

References 24 publications

Genotoxicity of acrylamide and its metabolite glycidamide administered in drinking water to male and female Big Blue mice

Genotoxicity of acrylamide and its metabolite glycidamide administered in drinking water to male and female Big Blue mice

Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

Differences in hemoglobin adduct levels of acrylamide in the general population with respect to dietary intake, smoking habits and gender

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