title: Genotoxicity of acrylamide and its metabolite glycidamide administered in drinking water to male and female Big Blue mice.
abstract: 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.
authors.affiliation: Division of Genetic and Reproductive Toxicology, US FDA/National Center for Toxicological Research, Jefferson, Arkansas 72079, USA. Mmanjanatha@nctr.fda.gov
authors.forename: Mugimane G
authors.initials: MG
authors.lastname: Manjanatha
authors.forename: Anane
authors.initials: A
authors.lastname: Aidoo
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Shelton
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Bishop
authors.forename: Lea P
authors.initials: LP
authors.lastname: McDaniel
authors.forename: Lascelles E
authors.initials: LE
authors.lastname: Lyn-Cook
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
mesh_terms: D020106:Acrylamide / Q000633:toxicity*; D000818:Animals; D004852:Epoxy Compounds / Q000633:toxicity*; D005260:Female; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics; D014881:Water Supply
chemical_list: D004852:Epoxy Compounds; D009153:Mutagens; D014157:Transcription Factors; D014764:Viral Proteins; C039000:cII protein, bacteriophage lambda; D020106:Acrylamide; C071834:glycidamide; D007041:Hypoxanthine Phosphoribosyltransferase