title: In vivo treatment with aflatoxin B1 increases DNA oxidation, base excision repair activity and 8-oxoguanine DNA glycosylase 1 levels in mouse lung.
abstract: Carcinogenicity of the mycotoxin aflatoxin B1 (AFB1), which is produced by Aspergillus fungi, is associated with bioactivation of AFB1 to AFB1-8,9-exo-epoxide and formation of DNA adducts. However, AFB1 also causes 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in mouse lung DNA, suggesting that oxidative DNA damage may also contribute to AFB1 carcinogenicity. The oxidative DNA damage 5-hydroxy-2'-deoxycytidine (5-OHdC) may also contribute to AFB1 carcinogenicity. The objective of the present study was to determine the effect of treatment of mice with AFB1 on pulmonary and hepatic: 8-OHdG and 5-OHdC levels; base excision repair (BER, which repairs oxidative DNA damage) activities; and on levels of 8-oxoguanine DNA glycosylase (OGG1, the rate-limiting enzyme in the BER of 8-OHdG). Female A/J mice were treated with vehicle (dimethyl sulfoxide) or 50 mg/kg AFB1 ip. Oxidative DNA damage was measured using HPLC with electrochemical detection, BER activity was assessed using an in vitro assay that employs a substrate plasmid DNA with 8-OHdG lesions, and OGG1 protein levels were determined by immunoblotting. Two hours post treatment, AFB1 increased 8-OHdG levels in mouse lung DNA by approximately 69% relative to control (p<0.05), but did not alter 8-OHdG levels in liver or 5-OHdC levels in lung or liver (p>0.05). AFB1 treatment also increased BER activity in mouse lung by approximately 87% (p<0.05) but did not affect hepatic BER activity (p>0.05). Levels of OGG1 immunoreactive protein were increased in both lung (20%) and liver (60%) (p<0.05). These results are consistent with oxidative DNA damage contributing to the carcinogenicity of AFB1 in this model.
authors.affiliation: Pharmacology and Toxicology Graduate Program, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Guindon-Kezis
authors.affiliation: Pharmacology and Toxicology Graduate Program, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Mulder
authors.affiliation: Pharmacology and Toxicology Graduate Program, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: masseyt@queensu.ca.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Massey
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects*; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism; D004563:Electrochemistry; D005260:Female; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008805:Mice, Inbred A; D009687:Nuclear Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010957:Plasmids / Q000187:drug effects
chemical_list: D002273:Carcinogens; D009687:Nuclear Proteins; D003841:Deoxycytidine; C074071:5-hydroxy-2'-deoxycytidine; D004247:DNA; D016604:Aflatoxin B1; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse
keywords: 8-Oxoguanine DNA glycosylase 1; Aflatoxin B(1); Base excision repair; Oxidative DNA damage