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Document Type:Latin Dissertation
Language of Document:English
Record Number:54654
Doc. No:TL24608
Call number:‭NR14041‬
Main Entry:Shengwen Shen
Title & Author:Arsenic effects on the formation and repair of benzo(a)pyrene diol epoxide-DNA adductsShengwen Shen
College:University of Alberta (Canada)
Date:2006
Degree:Ph.D.
student score:2006
Page No:182
Abstract:Arsenic, with its demonstrated cancerous and noncancerous effects, poses a tremendous health risk to human populations worldwide. In Bangladesh alone, 35 million people are currently exposed to high concentrations (greater than 50 μg/L) of inorganic arsenic (iAs) in drinking water. Although arsenic is an established human carcinogen, its mechanistic mode of carcinogenicity is far from clear. Arsenic may act in a co-mutagenic/co-carcinogenic mechanism. Amongst the proposed hypotheses regarding arsenic carcinogenicity, inhibition of DNA repair processes has been suggested as one predominant mechanism. However, the underlying mechanism responsible for DNA repair inhibition remains elusive. The objective of this thesis was to determine how arsenic modulates the formation and repair of DNA adducts induced by benzo(a)pyrene diol epoxide (BPDE) in human cells. A capillary electrophoresis-laser induced fluorescence (CE-LIF) based immunoassay was developed to measure BPDE-DNA adducts in human cells. The effects on the formation and repair of BPDE-DNA adducts by iAs and its metabolites were examined. In repair-deficient xeroderma pigmentosum group A (XPA) fibroblasts, arsenic pretreatment led to enhanced formation of BPDE-DNA adducts with trivalent arsenic compounds being more potent than pentavalent arsenic compounds. Most likely, arsenic exerted its enhancement by increasing cellular uptake of BPDE rather than by modulation of chromatin accessibility or by BPDE inactivation via the glutathione (GSH) conjugation system. In confluent repair-proficient normal human fibroblasts, the presence of arsenic inhibited the repair of BPDE-DNA adducts with trivalent arsenic compounds being more potent than pentavalent arsenic compounds. As the most potent inhibitor and a key metabolite of iAs, monomethylarsonous acid (MMA(III)) abrogated p53 accumulation induced by BPDE. More importantly, a striking temporal correlation between p53 expression and DNA repair capacity was observed. No similar correlations were found for repair proteins such as XPA, XPC and p62-TFIIH. p21 expression was modulated in a p53-dependent manner, implying that p53 was still functional and retained its wild-type conformation. Cell cycle analysis did not indicate that MMA(III) overrode the BPDE-induced G1/S arrest. Considering the well-demonstrated role of p53 in global genomic nucleotide excision repair (GG-NER), our results suggested that arsenic inhibited DNA repair by attenuating the expression of p53.
Subject:Health and environmental sciences; Adducts; Arsenic; Benzo(a)pyrene diol epoxide; DNA adducts; Public health; Toxicology; Deoxyribonucleic acid--DNA; 0573:Public health; 0383:Toxicology
Added Entry:University of Alberta (Canada)