Role of Age in Mitochondrial Susceptibility to 1,3-Dinitrobenzene-Induced Neurotoxicity.
dc.contributor.author | Kubik, Laura L. | en_US |
dc.date.accessioned | 2014-10-13T18:19:51Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2014-10-13T18:19:51Z | |
dc.date.issued | 2014 | en_US |
dc.date.submitted | 2014 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/108896 | |
dc.description.abstract | The prevalence of neurodegenerative disease is projected to increase in proportion to the doubling of older Americans over the coming decades. While age is the principle epidemiologic factor, it is likely that the development of these complex neuropathological entities is multifactorial and reflects the accumulation of chemical, physical and/or biological insults to the CNS. The Superfund chemical, 1,3-Dinitrobenzene (DNB), is an industrial intermediate in the production of dyes, plastics, and explosives. DNB selectively targets astrocytes in brainstem nuclei innervated by the 8th cranial nerve. The toxicity of DNB has been previously linked to dysfunction in astrocyte mitochondria. This study focuses on the susceptibility of key mitochondrial proteins to selective and specific oxidation following exposure to DNB in vitro and in vivo. Using an immortalized cortical astrocyte culture, passage number provided a useful surrogate for age in vitro. In a co-culture system containing immortalized astrocytes and primary neurons, low passage immortalized astrocytes are able to protect neurons in DNB exposure (whereas high passage immortalized astrocytes are not); additionally, low passage immortalized astrocytes are better able to survive DNB exposure in co-culture than high passage immortalized astrocytes. Additionally, in vivo data shows that proteins in older mitochondria are more susceptible to oxidation by DNB than the ones from young organelles, and mitochondria-related proteins are more highly expressed in young control animals than in older animals (both control and DNB-exposed). This data suggests that aging increases mitochondrial susceptibility to DNB-induced neurotoxicity. Using a high throughput proteomic approach with subsequent pathway analysis, it was determined that cation transmembrane transporter, nucleoside-triphosphatase, pyrophosphatase, and hydrolase activity pathways are selectively vulnerable to oxidation in older mitochondria. These results provide compelling evidence that environmental chemicals such as DNB may aid in the acceleration of injury to specific brain regions by inducing oxidation of sensitive mitochondrial proteins. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | 1,3-Dinitrobenzene | en_US |
dc.subject | Mitochondria | en_US |
dc.subject | Aging | en_US |
dc.subject | Neurotoxicity | en_US |
dc.title | Role of Age in Mitochondrial Susceptibility to 1,3-Dinitrobenzene-Induced Neurotoxicity. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Toxicology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Rozek, Laura Schnorenberg | en_US |
dc.contributor.committeemember | Philbert, Martin A. | en_US |
dc.contributor.committeemember | Gafni, Ari | en_US |
dc.contributor.committeemember | Richardson, Rudy J. | en_US |
dc.subject.hlbsecondlevel | Neurosciences | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/108896/1/lauramau_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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