The Oxidative Modification of Mitochondrial Proteins in 1,3-Dinitrobenzene Induced Neurotoxicity.
dc.contributor.author | Steiner, Stephen R. | en_US |
dc.date.accessioned | 2009-05-15T15:09:18Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2009-05-15T15:09:18Z | |
dc.date.issued | 2009 | en_US |
dc.date.submitted | en_US | |
dc.identifier.uri | https://hdl.handle.net/2027.42/62217 | |
dc.description.abstract | 1,3-DNB has widespread use in industry and the military as a chemical intermediate in the development of various plastics, dyes, and explosives. As a result, the production and improper disposal of various DNB-containing compounds has led to its status as a notable environmental contaminant. Acute exposure to 1,3-DNB leads to a variety of symptoms including methemoglobinemia, which can lead to nausea, vertigo, ataxia, and loss of cognition. Histopathological analysis of animals dosed with 1,3-DNB revealed the development of symmetrical, gliovascular lesions in specific brainstem nuclei. Increased oxidative stress, metabolic perturbation, and mitochondrial dysfunction in susceptible type 1 astrocytes are characteristics associated with 1,3-DNB-induced neurotoxicity. Through the use of confocal microscopy and proteomic analysis, this study demonstrated that 1,3-DNB-induced production of ROS led to loss of the mitochondrial membrane potential (ΔΨm), possibly mediated by the oxidative carbonylation of specific mitochondrial proteins in DI TNC1 astrocytes. Mitochondrial proteins were carbonylated within the first hour of 1,3-DNB exposure and pretreatment with antioxidants prior to 1,3-DNB exposure attenuates carbonylation. Protein carbonylation occurred prior to loss of ΔΨm, but concurrent with DNB-induced superoxide anion production. The number of proteins that were carbonylated is concentration-dependent and may reflect the relative sensitivity of specific amino acid residues toward oxidation. Tandem mass spectrometry confirmed the identity of specific mitochondrial and endoplasmic reticular proteins in sensitive to oxidation following exposure to 1,3-DNB. Cultured astrocytes (DI TNC1) exposed to metabolic/mitochondrial inhibitors (3-chloropropanediol and 3-nitropropionic acid) exhibited similar concentration-dependent deficits in metabolic activity and mitochondrial function. While there are differences in the range of proteins oxidized, a highly conserved core group of mitochondrial proteins appear to be highly susceptible to oxidation. These studies suggest that chemicals that induce energy deprivation syndromes in the brain may alter the function of a few key proteins that conspire to selectively injure brainstem astrocytes. | en_US |
dc.format.extent | 3677131 bytes | |
dc.format.extent | 1373 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.language.iso | en_US | en_US |
dc.subject | 1,3-dinitrobenzene | en_US |
dc.subject | 1,3-DNB | en_US |
dc.subject | Protein Carbonylation | en_US |
dc.subject | Oxidative Stress | en_US |
dc.subject | Mitochondria | en_US |
dc.title | The Oxidative Modification of Mitochondrial Proteins in 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 | Philbert, Martin A. | en_US |
dc.contributor.committeemember | Mancuso, Peter | en_US |
dc.contributor.committeemember | Osawa, Yoichi | en_US |
dc.contributor.committeemember | Welsh, Michael J. | en_US |
dc.subject.hlbsecondlevel | Biological Chemistry | en_US |
dc.subject.hlbsecondlevel | Neurosciences | en_US |
dc.subject.hlbsecondlevel | Public Health | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/62217/1/ssteinez_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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