DNA adduct formation and induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide or glycidamide†
Version of Record online: 19 NOV 2008
Copyright © 2009 Wiley-Liss, Inc.
International Journal of Cancer
Volume 124, Issue 9, pages 2006–2015, 1 May 2009
How to Cite
Von Tungeln, L. S., Churchwell, M. I., Doerge, D. R., Shaddock, J. G., McGarrity, L. J., Heflich, R. H., Gamboa da Costa, G., Marques, M. M. and Beland, F. A. (2009), DNA adduct formation and induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide or glycidamide. Int. J. Cancer, 124: 2006–2015. doi: 10.1002/ijc.24165
All of the authors, except Dr. M. Matilde Marques, are US government employees and performed this work as part of their official duties.
The opinions expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration.
The authors have quantified DNA adducts and the induction of micronuclei and mutations in newborn mice to elucidate the mechanisms by which the food contaminant acrylamide induces tumors. Their data indicate that a major pathway for mutation induction involves the metabolic conversion of acrylamide to the reactive electrophile glycidamide.
- Issue online: 24 FEB 2009
- Version of Record online: 19 NOV 2008
- Manuscript Accepted: 15 OCT 2008
- Manuscript Received: 11 JUL 2008
- National Institute for Environmental Health Sciences/National Toxicology Program. Grant Number: IAG number: 224-07-0007
- Fundação para a Ciência e a Tecnologia (FCT), Portugal
- DNA adducts;
Acrylamide, a food contaminant, is carcinogenic in experimental animals, with both genotoxic and nongenotoxic pathways being proposed. To obtain information regarding mechanisms of acrylamide tumorigenesis, we compared the extent of DNA adduct formation and induction of micronuclei and mutations in mice treated neonatally with acrylamide and its electrophilic metabolite glycidamide. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8 and 15 or PNDs 1–8 with 0.14 or 0.70 mmol acrylamide or glycidamide per kg body weight per day. One day after the final dose, B6C3F1/Tk+/+ mice were killed to measure DNA adduct levels and peripheral blood micronuclei. Three weeks after the last treatment, B6C3F1/Tk+/− mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. The levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine, the major glycidamide-DNA adduct, decreased in the order 0.70 mmol glycidamide > 0.70 mmol acrylamide > 0.14 mmol glycidamide ∼ 0.14 mmol acrylamide. Only glycidamide increased the frequency of micronucleated reticulocytes and normochromatic erythrocytes. In mice treated on PNDs 1, 8 and 15, the Hprt mutant frequency was increased by 0.70 mmol glycidamide. In mice dosed on PNDs 1–8, 0.70 mmol glycidamide caused extensive mortality; each of the other treatments increased the Tk mutant frequency, whereas acrylamide increased the Hprt mutant frequency. These data suggest that the mutagenic response in neonatal mice treated on PNDs 1, 8 and 15 is due to glycidamide, whereas mutations resulting from dosing on PNDs 1–8 are due to another mechanism. © 2008 Wiley-Liss, Inc.