DNA adduct formation and induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide or glycidamide.
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 approximately 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.
Von Tungeln
Linda S
LS
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Churchwell
Mona I
MI
Doerge
Daniel R
DR
Shaddock
Joseph G
JG
McGarrity
Lynda J
LJ
Heflich
Robert H
RH
Gamboa da Costa
Gonçalo
G
Marques
M Matilde
MM
Beland
Frederick A
FA
D020106:Acrylamide / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects*; D004852:Epoxy Compounds / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D019656:Loss of Heterozygosity; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009154:Mutation / Q000235:genetics*; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics*
D018736:DNA Adducts; D004852:Epoxy Compounds; D020106:Acrylamide; C071834:glycidamide; D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase