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dc.contributor.authorMulder, Jeanne Elizabehen
dc.date2013-10-10 15:14:30.042
dc.date2013-10-17 22:04:14.261
dc.date2013-10-17 22:24:31.577
dc.date.accessioned2013-10-18T15:03:37Z
dc.date.available2015-03-01T09:00:17Z
dc.date.issued2013-10-18
dc.identifier.urihttp://hdl.handle.net/1974/8427
dc.descriptionThesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2013-10-17 22:24:31.577en
dc.description.abstractThe studies described in this thesis investigated the relationship between DNA repair mechanisms, aflatoxin B1 (AFB1)-induced DNA damage and carcinogenesis. Mice deficient in 8-oxoguanine glycosylase (OGG1, the rate-limiting enzyme in repair of oxidized guanine), mice heterozygous for OGG1, and wild type mice, were exposed to a single tumourigenic dose (50 mg/kg) of AFB1. Neither ogg1 genotype nor AFB1 treatment affected levels of oxidized guanine in lung or liver 2 h post-treatment. ogg1 (-/-) mice had increased susceptibility to AFB1 toxicity, as reflected by increased mortality within one week of AFB1 exposure. AFB1 treatment did not significantly increase lung or liver tumourigenesis compared to DMSO controls. No difference was observed between ogg1 genotypes, although a non-significant trend towards AFB1-treated ogg1 (-/-) mice being more susceptible to tumourigenicity was apparent. Overall, deletion of ogg1 did not significantly affect AFB1-induced DNA damage or tumourigenicity, suggesting that oxidized guanine may not be a major contributor to AFB1-induced tumourigenesis. The effects of AFB1 on DNA repair were assessed in p53 (a protein implicated in regulation of DNA repair) wild type and heterozygous mice. p53 (+/+) mice treated with 0, 0.2 or 1.0 ppm AFB1 for 26 weeks had increased nucleotide excision repair (NER) activities in lung and liver compared to control, which may represent an adaptive response to AFB1-derived DNA adducts. In p53 (+/-) mice, the AFB1-induced increase in NER was significantly attenuated, suggesting that loss of one allele of p53 limits the ability of NER to up-regulate in response to AFB1-induced DNA damage. Twenty-six week exposure to AFB1 did not affect base excision repair (BER) in p53 (+/+) mouse lung or liver compared to control. BER was significantly decreased in livers from mice exposed to 1.0 ppm AFB1 compared to those exposed to 0.2 ppm AFB1, a result that was not due to liver cell death or to altered levels of OGG1 protein. In lungs and livers of p53 (+/-) mice, BER activity was unchanged by AFB1. As such, the difference in BER response between 0.2 ppm and 1.0 ppm AFB1 treatment seen in the p53 (+/+) mice appears to be p53 dependent.en
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectAflatoxin B1en
dc.subjectCarcinogenesisen
dc.subjectBase Excision Repairen
dc.subject8-oxoguanine glycosylase 1en
dc.subjectOxidative DNA Damageen
dc.subjectNucleotide Excision Repairen
dc.subjectp53en
dc.titleDNA Repair Mechanisms, Aflatoxin B1-Induced DNA Damage and Carcinogenesisen
dc.typethesisen
dc.description.restricted-thesisThis thesis is to be restricted until all research chapters have been published.en
dc.description.degreePhDen
dc.contributor.supervisorMassey, Thomas E.en
dc.contributor.departmentPharmacology and Toxicologyen
dc.embargo.terms1825en
dc.degree.grantorQueen's University at Kingstonen


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