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 seleniums 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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-09292008-134837 |
| Date | 30 September 2008 |
| Creators | Morgan, Kathleen L. |
| Contributors | Miguel Estevez, MD, PhD, Stephen Grant, PhD, A. Paula Monaghan-Nichols, PhD, Robert Bowser, PhD, Lewis Jacobson, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-09292008-134837/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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