DNA damage and DNA adduct formation in rat tissues following oral administration of acrylamide.
Acrylamide is present as a contaminant in the human diet in heated food products. It has been found to be carcinogenic in laboratory rats and has been classified as probably carcinogenic in humans. In order to clarify the possible involvement of a primary genotoxic mechanism in acrylamide-induced carcinogenicity, both the presence of DNA damage, measured by the comet assay, and the formation of N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua) and N3-(2-carbamoyl-2-hydroxyethyl)adenine (N3-GA-Ade), derived from reaction of the active metabolite glycidamide (GA) with the DNA, analyzed by LC/MS/MS, were assessed in selected rat tissues. Rats were administered with single oral doses of acrylamide (18, 36 or 54 mg/kg body weight (b.w.) and the organs (blood leukocytes, brain, bone marrow, liver, testes and adrenals) were sampled at different times after treatment. Results from GA-induced DNA adduct measurements indicated a relatively even organ distribution of the adducts in brain, testes and liver. Organ-specificity in acrylamide carcinogenesis can therefore not be explained by a selective accumulation of GA-DNA adducts in the target organs, at least not after a single dose exposure. The DNA adduct profiles and half-lives were similar in the different organs; except that the N3-GA-Ade adduct was more rapidly removed from tissues than the N7-GA-Gua adduct. Increased extent of DNA migration, as measured by the in vivo rat comet assay, was found in brain and testes, and these specific results seem to be in accordance with the known organ-specificity in acrylamide carcinogenesis in rat. Only weak and transient DNA damage was recorded in the liver, bone marrow and adrenals. The DNA-damaging effect of the compound observed in the blood leukocytes could be a simple biomarker of acrylamide exposure and genotoxicity.
Manière
Isabelle
I
Agence Française de Sécurité Sanitaire des Aliments, Laboratoire d'Etudes et de Recherches sur les Médicaments Vétérinaires et les Désinfectants, BP 90203, 35302 Fougères Cedex, France. i.maniere@fougeres.afssa.fr
Godard
Thierry
T
Doerge
Daniel R
DR
Churchwell
Mona I
MI
Guffroy
Magali
M
Laurentie
Michel
M
Poul
Jean-Michel
JM
D020106:Acrylamide / Q000378:metabolism / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D020552:Comet Assay; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D008297:Male; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
D018736:DNA Adducts; D009153:Mutagens; D020106:Acrylamide