Genomic Response in Human Urothelial Cells Exposed Chronically to Monomethylarsonous Acid

Persistent Link:
http://hdl.handle.net/10150/299107
Title:
Genomic Response in Human Urothelial Cells Exposed Chronically to Monomethylarsonous Acid
Author:
Medeiros, Matthew Keane
Issue Date:
2013
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Bladder cancer has been associated with chronic arsenic exposure. Monomethylarsonous acid [MMA(III)] is a metabolite of inorganic arsenic biotransformation and has been shown to transform an immortalized urothelial cell line (UROtsa) at a concentration 20-fold less than arsenite. MMA(III) was used as a model arsenical to examine the mechanisms of arsenical-induced transformation of the urothelium. A microarray analysis was performed to assess the transcriptional changes in UROtsa during the critical window of chronic MMA(III) exposure that leads to transformation at three months time. The analysis revealed only minor changes in gene expression at one and two months of exposure, contrasting with substantial changes observed at three months of exposure. The gene expression changes at three months were analyzed showing distinct alterations in biological processes and pathways such as a response to oxidative stress, enhanced cell proliferation, anti-apoptosis, MAPK signaling, as well as inflammation. To address the lack of information between two and three months of exposure -- the critical period of transformation -- the expression of selected pathway marker genes were measured by PCR array analysis on a weekly and monthly basis. A very similar pattern of altered expression of these genes was observed when compared to microarray results, and suggested early perturbations in cell signaling cascades, immunological pathways, cytokine expression, and MAPK pathway, are particularly important in driving malignant transformation. These results showed a strong association between the acquired phenotypic changes that occurred as early as one to two months of chronic MMA(III) exposure, and gene expression patterns that are indicative of the earliest stages in carcinogenesis. Additionally, studies on the effects of withdrawal of arsenical were also conducted and showed that phenotypic changes persisted even in the absence of arsenical; that gene expression patterns of pathway marker genes, those that showed significant alterations between 3 and 6 months of exposure, appeared to normalize after withdrawal of the arsenical.
Type:
text; Electronic Dissertation
Keywords:
bladder; cancer biology; gene expression; gene microarray; urothelial cells; Pharmacology & Toxicology; arsenic
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology & Toxicology
Degree Grantor:
University of Arizona
Advisor:
Gandolfi, A. Jay

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleGenomic Response in Human Urothelial Cells Exposed Chronically to Monomethylarsonous Aciden_US
dc.creatorMedeiros, Matthew Keaneen_US
dc.contributor.authorMedeiros, Matthew Keaneen_US
dc.date.issued2013-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractBladder cancer has been associated with chronic arsenic exposure. Monomethylarsonous acid [MMA(III)] is a metabolite of inorganic arsenic biotransformation and has been shown to transform an immortalized urothelial cell line (UROtsa) at a concentration 20-fold less than arsenite. MMA(III) was used as a model arsenical to examine the mechanisms of arsenical-induced transformation of the urothelium. A microarray analysis was performed to assess the transcriptional changes in UROtsa during the critical window of chronic MMA(III) exposure that leads to transformation at three months time. The analysis revealed only minor changes in gene expression at one and two months of exposure, contrasting with substantial changes observed at three months of exposure. The gene expression changes at three months were analyzed showing distinct alterations in biological processes and pathways such as a response to oxidative stress, enhanced cell proliferation, anti-apoptosis, MAPK signaling, as well as inflammation. To address the lack of information between two and three months of exposure -- the critical period of transformation -- the expression of selected pathway marker genes were measured by PCR array analysis on a weekly and monthly basis. A very similar pattern of altered expression of these genes was observed when compared to microarray results, and suggested early perturbations in cell signaling cascades, immunological pathways, cytokine expression, and MAPK pathway, are particularly important in driving malignant transformation. These results showed a strong association between the acquired phenotypic changes that occurred as early as one to two months of chronic MMA(III) exposure, and gene expression patterns that are indicative of the earliest stages in carcinogenesis. Additionally, studies on the effects of withdrawal of arsenical were also conducted and showed that phenotypic changes persisted even in the absence of arsenical; that gene expression patterns of pathway marker genes, those that showed significant alterations between 3 and 6 months of exposure, appeared to normalize after withdrawal of the arsenical.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectbladderen_US
dc.subjectcancer biologyen_US
dc.subjectgene expressionen_US
dc.subjectgene microarrayen_US
dc.subjecturothelial cellsen_US
dc.subjectPharmacology & Toxicologyen_US
dc.subjectarsenicen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorGandolfi, A. Jayen_US
dc.contributor.committeememberFutscher, Bernard W.en_US
dc.contributor.committeememberTischler, Marc E.en_US
dc.contributor.committeememberChen, Yinen_US
dc.contributor.committeememberZhang, Donnaen_US
dc.contributor.committeememberGandolfi, A. Jayen_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.