title: Effect of 8-oxoguanine glycosylase deficiency on aflatoxin B1 tumourigenicity in mice.
abstract: The mycotoxin aflatoxin B1 (AFB1) may initiate cancer by causing oxidatively damaged DNA, specifically by causing 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) lesions. Base excision repair removes these lesions, with 8-oxoguanine glycosylase (OGG1) being the rate-limiting enzyme. The aim of this study was to determine the effect of ogg1 deficiency on AFB1-induced oxidatively damaged DNA and tumourigenesis. Female wild-type, heterozygous and homozygous ogg1 null mice were given a single dose of 50mg/kg AFB1 or 40 µl dimethyl sulfoxide (DMSO) ip. Neither ogg1 genotype nor AFB1 treatment affected levels of oxidised guanine in lung or liver 2h post-treatment. AFB1-treated ogg1 null mice showed exacerbated weight loss and mortality relative to DMSO-treated ogg1 null mice, but AFB1 treatment did not significantly increase lung or liver tumour incidence compared with controls, regardless of ogg1 genotype. Suspect lung masses from three of the AFB1-treated mice were adenomas, and masses from two of the mice were osteosarcomas. No osteosarcomas were observed in DMSO-treated mice. All liver masses from AFB1-treated mice were adenomas, and one also contained a hepatocellular carcinoma. In DNA from the lung tumours, the K-ras mutation pattern was inconsistent with initiation by AFB1. In conclusion, ogg1 status did not have a significant effect on AFB1-induced oxidatively damaged DNA or tumourigenesis, but deletion of one or both alleles of ogg1 did increase susceptibility to other aspects of AFB1 toxicity.
authors.affiliation: Department of Biomedical and Molecular Sciences, Pharmacology and Toxicology Graduate Program, Queen's University, Rm 556, Botterell Hall, Kingston, Ontario K7L 3N6, Canada, Department of Pathobiology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Mulder
authors.affiliation: Department of Pathobiology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Turner
authors.affiliation: Department of Biomedical and Molecular Sciences, Pharmacology and Toxicology Graduate Program, Queen's University, Rm 556, Botterell Hall, Kingston, Ontario K7L 3N6, Canada, Department of Pathobiology, University of Guelph, Guelph, Ontario N1G 2W1, Canada masseyt@queensu.ca.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Massey
mesh_terms: D000236:Adenoma / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics*; D005260:Female; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D002273:Carcinogens; D016604:Aflatoxin B1; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse