title: Acrylamide-induced carcinogenicity in mouse lung involves mutagenicity: cII gene mutations in the lung of big blue mice exposed to acrylamide and glycidamide for up to 4 weeks.
abstract: Potential health risks for humans from exposure to acrylamide (AA) and its epoxide metabolite glycidamide (GA) have garnered much attention lately because substantial amounts of AA are present in a variety of fried and baked starchy foods. AA is tumorigenic in rodents, and a large number of in vitro and in vivo studies indicate that AA is genotoxic. A recent cancer bioassay on AA demonstrated that the lung was one of the target organs for tumor induction in mice; however, the mutagenicity of AA in this tissue is unclear. Therefore, to investigate whether or not gene mutation is involved in the etiology of AA- or GA-induced mouse lung carcinogenicity, we screened for cII mutant frequency (MF) in lungs from male and female Big Blue (BB) mice administered 0, 1.4, and 7.0 mM AA or GA in drinking water for up to 4 weeks (19-111 mg/kg bw/days). Both doses of AA and GA produced significant increases in cII MFs, with the high doses producing responses 2.7-5.6-fold higher than the corresponding controls (P ≤ 0.05; control MFs = 17.2 ± 2.2 and 15.8 ± 3.5 × 10(-6) in males and females, respectively). Molecular analysis of the mutants from high doses indicated that AA and GA produced similar mutation spectra and that these spectra were significantly different from the spectra in control mice (P ≤ 0.01). The predominant types of mutations in the lung cII gene from AA- and GA-treated mice were A:T → T:A, and G:C → C:G transversions, and -1/+1 frameshifts at a homopolymeric run of Gs. The MFs and types of mutations induced by AA and GA in the lung are consistent with AA exerting its genotoxicity via metabolism to GA. These results suggest that AA is a mutagenic carcinogen in mouse lungs and therefore further studies on its potential health risk to humans are warranted. Environ. Mol. Mutagen. 56:446-456, 2015. © 2015 Wiley Periodicals, Inc.
authors: Division of Genetic and Molecular Toxicology, US FDA, National Center for Toxicological Research, Jefferson, Arkansas.
authors: Mugimane G
authors: MG
authors: Manjanatha
authors: Division of Genetic and Molecular Toxicology, US FDA, National Center for Toxicological Research, Jefferson, Arkansas.
authors: Li-Wu
authors: LW
authors: Guo
authors: Division of Genetic and Molecular Toxicology, US FDA, National Center for Toxicological Research, Jefferson, Arkansas.
authors: Sharon D
authors: SD
authors: Shelton
authors: Division of Biochemical Toxicology, US FDA, National Center for Toxicological Research, Jefferson, Arkansas.
authors: Daniel R
authors: DR
authors: Doerge
mesh_terms: D020106:Acrylamide / Q000378:metabolism / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008815:Mice, Inbred Strains; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009154:Mutation; D017422:Sequence Analysis, DNA; D012727:Sex Characteristics; D014157:Transcription Factors / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D004852:Epoxy Compounds; D009153:Mutagens; D014157:Transcription Factors; D014764:Viral Proteins; C039000:cII protein, bacteriophage lambda; D020106:Acrylamide; C071834:glycidamide; D004247:DNA
keywords: DNA adducts; acrylamide; cII mutant frequency; carcinogenicity; glycidamide