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Permanent link (DOI): https://doi.org/10.7939/R3RN30G6J

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Cytotoxicity, mutagenicity, and genotoxicity of emerging drinking water disinfection byproducts Open Access

Descriptions

Other title
Subject/Keyword
drinking water disinfection byproducts
method development
cytotoxicity
in vitro methods
genotoxicity
real-time cell analysis
mutagenicity
toxicology
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
McGuigan, Claire Frances
Supervisor and department
Li, Xing-Fang (Laboratory Medicine and Pathology)
Le, X. Chris (Laboratory Medicine and Pathology)
Examining committee member and department
Plewa, Michael (Crop Sciences, University of Illinois at Urbana-Champaign)
Martin, Jonathan (Laboratory Medicine and Pathology)
Leslie, Elaine (Physiology)
Weinfeld, Michael (Oncology)
Department
Medical Sciences- Laboratory Medicine and Pathology
Specialization

Date accepted
2013-12-23T14:16:14Z
Graduation date
2014-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Drinking water disinfection byproducts (DBPs) are formed unintentionally when organic matter in raw water reacts with disinfectants used to kill pathogens. Epidemiological studies have shown that an increased risk of bladder cancer is associated with consumption of chlorinated water, but little is known of the toxicity of many DBPs. This thesis examined the cytotoxic, mutagenic, and genotoxic properties of phenazine and halobenzoquinone (HBQ) DBPs in human cells. Cytotoxicity was examined with an impedance-based real-time cell analysis (RTCA) instrument, mutagenicity was examined with the Ames test (bacterial reverse mutation assay), and genotoxicity was examined with the alkaline comet assay. Phenazine showed differential toxicity in human cell lines, producing an antiproliferative cytotoxic effect in HepG2 cells but a genotoxic effect in T24 cells. The BJ/XPA RTCA in vitro assay was developed and validated to provide high-throughput screening of cytotoxicity and nucleotide excision repair (NER)-mediated DNA damage simultaneously. Selected HBQs were examined with the BJ/XPA assay; the position, type, and number of substitutions on the benzoquinone ring affected cytotoxicity. All tested HBQs caused substitution mutations in the Ames test under at least some of the experimental conditions. 2,6-dichloro-3-methyl-1,4-benzoquinone (DCMBQ) was the most potent HBQ compound tested, demonstrating cytotoxicity, mutagenicity, and genotoxicity. Follow-up experiments indicated that N-acetylcysteine, a ROS scavenger, reduced cytotoxicity and genotoxicity when added concomitantly with DCMBQ. Both the cytotoxic and genotoxic effects of DCMBQ appeared to be mediated, at least in part, by the formation of reactive oxygen species. DCMBQ-induced genotoxicity appeared to be refractory to repair and may involve formation of complex oxidatively generated clustered lesions. Additional in vitro and in vivo studies are required for HBQ DBPs, particularly DCMBQ, to further determine their toxic effects. In summary, the original contributions of this research are: 1) the development of a novel in vitro method to simultaneously assess cytotoxicity and NER-mediated genotoxicity; 2) new information on the cytotoxic, mutagenic, and genotoxic properties of halobenzoquinone DBPs; 3) discovery of cytotoxic and genotoxic properties of phenazine; and 4) evidence of potential toxic mechanisms of action of DCMBQ.
Language
English
DOI
doi:10.7939/R3RN30G6J
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Moe B, McGuigan CF, Dabek-Zlotorzynska E, Gabos S, Li XF. 2013. Encyclopedia of Analytical Chemistry. Hoboken, NJ: John Wiley and Sons, Inc.McGuigan CF & Li XF. 2014. Cytotoxicity and genotoxicity of phenazine in two human cell lines. Toxicology In Vitro. (Accepted, in press.)

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