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Genetic and Pharmacologic analysis of the Mechanisms of Selenium toxicity in Caenorhabditis elegans

Morgan, Kathleen L. (2008) Genetic and Pharmacologic analysis of the Mechanisms of Selenium toxicity in Caenorhabditis elegans. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Selenium is an essential nutrient that is beneficial at daily intakes of 50-200μg/day and is detrimental at intake rates beyond 800μg/day. Selenium toxicity is an increasing environmental problem due to being a waste product of metal, coal, and oil refining. High selenium exposure causes developmental defects in wildlife, motor neuron degeneration in livestock and has been epidemiologically associated with the human motor neuron disease amyotrophic lateral sclerosis (ALS). In order to begin to define the cellular damage pathways activated by selenium, we have developed a genetic model of selenium toxicity using Caenorhabditis elegans. In this dissertation, we have begun to identify both environmental and genetic factors that affect selenium toxicity (like temperature, bacterial metabolism from the food source, calcium in the media), as well as a potential source of selenium's toxic effects, an increase in reactive oxygen species. We have also begun to determine which potential mechanism(s) of cell death are activated using strains with reduction-of-function mutations in cell death genes and pharmacologic treatments. In the second part of thesis, we characterize the neuronal damage caused by selenium because of its potential disease relevance. We demonstrate that selenium toxicity causes a decrease in cholinergic signaling that results in increased cytosolic protein catabolism in muscle which is predictably suppressed by nicotinic agonists and the acetylcholinesterase inhibitors. Combined, these data demonstrate that selenium toxicity causes muscle denervation, mimicking the pathology observed in ALS. We also demonstrate that selenium causes similar denervation of the muscles mediating egg-laying in C. elegans. Finally, we have investigated oxidative stress pathways regulated by DAF-2, a major stress response pathway in C. elegans, and identified a gene target of DAF-2 regulation, an iron-manganese superoxide dismutase (sod-2), that is a "protective factor" affecting sensitivity to selenium. This work demonstrates that selenium-related oxidative stress causes a progressive movement impairment due to motor neuron injury.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Morgan, Kathleen
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairEstevez,
Committee MemberMonaghan-Nichols, A. Paulamonaghan@pitt.eduMONAGHAN
Committee MemberJacobson, Lewisljac@pitt.eduLJAC
Committee MemberBowser,
Committee MemberGrant,
Date: 30 September 2008
Date Type: Completion
Defense Date: 4 September 2008
Approval Date: 30 September 2008
Submission Date: 29 September 2008
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biochemistry and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: amyotrophic lateral sclerosis; Caenorhabditis elegans; insulin signaling; neurodegeneration; reactive oxygen species; selenium toxicity
Other ID:, etd-09292008-134837
Date Deposited: 10 Nov 2011 20:02
Last Modified: 15 Nov 2016 13:50


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