Investigating the Mechanisms of Toxicity of Benzene and its Metabolite Benzoquinone and the Role of Sulforaphane as a Potential Protective Agent in CD-1 Mouse Development

dc.contributor.authorPhilbrook, Nicolaen
dc.contributor.departmentPharmacology and Toxicologyen
dc.contributor.supervisorWinn, Louise M.en
dc.date2015-06-29 09:36:44.339
dc.date.accessioned2015-06-30T19:51:22Z
dc.date.available2015-12-20T09:00:05Z
dc.date.issued2015-06-30
dc.degree.grantorQueen's University at Kingstonen
dc.descriptionThesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2015-06-29 09:36:44.339en
dc.description.abstractBenzene is an environmental pollutant and a known human leukemogen. It is also suspected to be associated with in utero-initiated leukemia. However, the mechanisms of benzene-mediated toxicity and carcinogenicity in both adults and fetuses are not well understood. Two main research hypotheses were tested in this thesis work. The first was that exposure to the benzene metabolite, benzoquinone, leads to increased levels of reactive oxygen species (ROS) and DNA damage in cultured mouse fetal liver cells, and that epigenetic changes in CD-1 mouse fetal livers would result from in vivo exposure to benzene. The second was that exposure to the phytochemical, sulforaphane (SFN), would induce detoxification enzymes in CD-1 mouse fetal livers in vitro and in vivo, and that this would confer protection against benzene-induced cellular damage. Our data demonstrated that exposure to benzoquinone increased ROS levels, increased DNA damage, and altered DNA repair gene expression in cultured CD-1 mouse fetal liver cells. Additionally, although we found that SFN induced various metabolizing enzymes involved in the detoxification of benzene metabolites, SFN did not protect against the deleterious effects of benzene found in this study. In a separate study, we examined whether SFN could induce fetal and/or maternal enzymes involved in benzene detoxification in vivo in CD-1 mice and how this compared to non-pregnant CD-1 mice. While we found that chronic SFN exposure induced both gene expression and activity of liver detoxification enzymes of both pregnant and non-pregnant mice, SFN had no effect on expression levels or activity of these genes in fetal livers exposed in utero. Lastly, we investigated the effect of benzene exposure on DNA methylation and histone modifications in vivo. Benzene exposure decreased global DNA methylation in maternal bone marrow only, having no effect on any other epigenetic modifications measured in these studies. Taken together, the data presented in this thesis only partially supported our hypotheses; nevertheless, they provide valuable information for future research directions pertaining to benzene-associated transplacental carcinogenesis.en
dc.description.degreePhDen
dc.description.restricted-thesisNot all the chapters have been accepted for publication, and we do not want online publishing of this thesis to affect that process.en
dc.embargo.terms1825en
dc.identifier.urihttp://hdl.handle.net/1974/13377
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsCreative Commons - Attribution - CC BYen
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.subjectbenzeneen
dc.subjectsulforaphaneen
dc.subjectdevelopmental toxicityen
dc.subjectCD-1 miceen
dc.titleInvestigating the Mechanisms of Toxicity of Benzene and its Metabolite Benzoquinone and the Role of Sulforaphane as a Potential Protective Agent in CD-1 Mouse Developmenten
dc.typethesisen
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