Adenomatous polyposis coli influences micronuclei induction by PhIP and acrylamide in mouse erythrocytes.
Micronucleus (MN) induction in erythrocytes of multiple intestinal neoplasia (Min) mice with heterozygous Apc mutation was measured after s.c. injections of acrylamide, glycidamide, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and colchicine, and compared with wild-type (wt) mice. Since Apc influences microtubule dynamics, we wanted to test whether Min-mice were more sensitive to the production of MN than wild-type mice. We also examined the effect of pre-treatment with cytosine beta-D-arabinofuranoside (Ara C) and hydroxyurea, which inhibit ligation of DNA strand breaks in the repair of DNA adducts. All compounds induced a significant increase in MN in both strains of mice with the following potencies: acrylamide<glycidamide<PhIP. No difference in the induction of MN was seen between Min-mice and wt-mice exposed to acrylamide, glycidamide or colchicine without pre-treatment. However, in Min-mice, PhIP treatment induced much less MN than in wt-mice, with about four- and six-fold increase in MN in Min-mice and wt-mice, respectively. A reduced ability to repair PhIP adducts may be the reason for the lower induction of MN in Min-mice. Treatment with Ara C and hydroxyurea, to increase sensitivity, gave more than a four-fold increase in MN, but strongly reduced proliferation. Pre-treatment with Ara C and hydroxyurea made the Min-mice slightly more sensitive to MN induction by glycidamide compared to wt-mice. We conclude that Min-mice are less sensitive than wt-mice to MN induction by PhIP that forms bulky DNA adducts, while Min-mice and wt-mice are equally sensitive to MN induction by acrylamide and glycidamide that form DNA base adducts.
Husøy
T
T
Department of Food Toxicology, Norwegian Institute of Public Health, PO Box 4404, Nydalen, NO-0403 Oslo, Norway. trine.husoy@fhi.no
Abramsson-Zetterberg
L
L
Ølstørn
H B
HB
Paulsen
J E
JE
Alexander
J
J
D020106:Acrylamide / Q000633:toxicity*; D011125:Adenomatous Polyposis Coli / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D003078:Colchicine / Q000633:toxicity; D003561:Cytarabine / Q000494:pharmacology; D018736:DNA Adducts / Q000378:metabolism; D004852:Epoxy Compounds / Q000633:toxicity; D004912:Erythrocytes / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006918:Hydroxyurea / Q000494:pharmacology; D007093:Imidazoles / Q000633:toxicity*; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*
D025601:Adenomatous Polyposis Coli Protein; D018736:DNA Adducts; D004852:Epoxy Compounds; D007093:Imidazoles; D009153:Mutagens; D003561:Cytarabine; D020106:Acrylamide; C071834:glycidamide; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D003078:Colchicine; D006918:Hydroxyurea