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Adenomatous polyposis coli influences micronuclei induction by PhIP and acrylamide in mouse erythrocytes
T Husøy1, L Abramsson-Zetterberg, H B Ølstørn
1Department of Food Toxicology, Norwegian Institute of Public Health, PO Box 4404, Nydalen, NO-0403 Oslo, Norway. trine.husoy@fhi.no
Abstract:
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
Insights
Multiple Intestinal Neoplasia (Min) mice showed varying sensitivity to genotoxic agents compared to wild-type mice. Min mice were less sensitive to PhIP-induced micronuclei, suggesting impaired DNA repair.
Area of Science:
- Genetics and Molecular Biology
- Toxicology
- Cancer Research
Background:
- The Apc gene mutation in Multiple Intestinal Neoplasia (Min) mice affects microtubule dynamics.
- Investigating differential sensitivity to genotoxic agents in Min mice versus wild-type (wt) mice is crucial for understanding cancer predisposition.
- Understanding DNA repair mechanisms in response to specific chemical exposures is vital for risk assessment.
Purpose of the Study:
- To compare the induction of micronuclei (MN) in Min mice and wt mice after exposure to acrylamide, glycidamide, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and colchicine.
- To determine if Min mice exhibit increased sensitivity to MN induction due to their heterozygous Apc mutation.
- To evaluate the effect of pre-treatment with DNA repair inhibitors (cytosine beta-D-arabinofuranoside [Ara C] and hydroxyurea) on MN induction.
Main Methods:
- Subcutaneous injections of genotoxic compounds (acrylamide, glycidamide, PhIP, colchicine) were administered to Min and wt mice.
- Micronucleus (MN) formation in erythrocytes was quantified as a measure of genotoxicity.
- Mice were pre-treated with Ara C and hydroxyurea to assess their impact on MN induction and DNA repair inhibition.
Main Results:
- All tested compounds significantly increased MN in both mouse strains, with potencies ordered as acrylamide < glycidamide < PhIP.
- No significant difference in MN induction was observed between Min and wt mice for acrylamide, glycidamide, or colchicine without pre-treatment.
- Min mice showed significantly lower MN induction by PhIP compared to wt mice, suggesting a reduced ability to repair PhIP-induced DNA adducts. Pre-treatment with Ara C and hydroxyurea increased sensitivity to glycidamide in Min mice but reduced proliferation.
Conclusions:
- Min mice are less sensitive than wt mice to MN induction by PhIP, which forms bulky DNA adducts, indicating a potential defect in repairing such adducts.
- Min and wt mice exhibit equal sensitivity to MN induction by acrylamide and glycidamide, which form DNA base adducts.
- The Apc mutation in Min mice influences sensitivity to specific types of genotoxic damage, particularly those involving bulky DNA adducts.
