title: Differential genotoxicity of acrylamide in the micronucleus and Pig-a gene mutation assays in F344 rats and B6C3F1 mice.
abstract: Acrylamide is used in many industrial processes and is present in a variety of fried and baked foods. In rodent carcinogenicity assays, acrylamide exposure leads to tumour formation at doses lower than those demonstrated to induce genotoxic damage. We evaluated the potential of acrylamide to induce structural DNA damage and gene mutations in rodents using highly sensitive flow cytometric analysis of micronucleus and Pig-a mutant frequencies, respectively. Male F344 rats and B6C3F1 mice were administered acrylamide in drinking water for 30 days at doses spanning and exceeding the range of acrylamide exposure tested in cancer bioassays-top dose of 12.0 and 24.0mg/kg/day in mice and in rats, respectively. A positive control, N-ethyl-N-nitrosourea, was administered at the beginning and end of the study to meet the expression time for the two DNA damage phenotypes. The results of the micronucleus and Pig-a assays were negative and equivocal, respectively, for male rats exposed to acrylamide at the concentrations tested. In contrast, acrylamide induced a dose-dependent increase in micronucleus formation but tested negative in the Pig-a assay in mice. Higher plasma concentrations of glycidamide in mice than rats are hypothesized to explain, at least in part, the differences in the response. Benchmark dose modelling indicates that structural DNA damage as opposed to point mutations is most relevant to the genotoxic mode of action of acrylamide-induced carcinogenicity. Moreover, the lack of genotoxicity detected at <6.0mg/kg/day is consistent with the notion that non-genotoxic mechanisms contribute to acrylamide-induced carcinogenicity in rodents.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hobbs
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Davis
authors.forename: Kim
authors.initials: K
authors.lastname: Shepard
authors.forename: Nikolai
authors.initials: N
authors.lastname: Chepelev
authors.affiliation: SNF SAS, rue Adrienne Bolland, ZAC de Milieux, 42163 Andrézieux, France.
authors.forename: Marvin
authors.initials: M
authors.lastname: Friedman
authors.affiliation: SNF SAS, rue Adrienne Bolland, ZAC de Milieux, 42163 Andrézieux, France.
authors.forename: Dennis
authors.initials: D
authors.lastname: Marroni
authors.forename: Leslie
authors.initials: L
authors.lastname: Recio
mesh_terms: D020106:Acrylamide / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D009152:Mutagenicity Tests; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D020106:Acrylamide; D004247:DNA