Mechanisms of Prediction and Potential Causation of Organophosphate Induced Delayed Neurotoxicity.
dc.contributor.author | Hein, Nichole DeEtta | en_US |
dc.date.accessioned | 2009-09-03T14:50:54Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2009-09-03T14:50:54Z | |
dc.date.issued | 2009 | en_US |
dc.date.submitted | en_US | |
dc.identifier.uri | https://hdl.handle.net/2027.42/63785 | |
dc.description.abstract | Organophosphorus (OP) compounds, used in insecticides, pharmaceuticals, and weapons of biochemical warfare inhibit serine hydrolases. Exposure to OP compounds has shown that a phosphylation of certain serine esterases results in two distinct types of toxicities: an acute cholinergic toxicity associated with inhibition of acetylcholinesterase (AChE), and a more chronic toxicity associated with the inhibition and aging of neuropathy target esterase (NTE). OP induced delayed neurotoxicity (OPIDN) occurs when a threshold of NTE is inhibited and aged, and is characterized by axonopathies in the peripheral and central nervous systems 1-4 weeks after exposure. An accurate in vivo model of OPIDN is difficult to develop, due to interspecies variations of inhibitor sensitivity and metabolism. Understanding the mechanism of inhibition and aging of serine esterases by OP compounds and correlating this with pathological axonopathies are important for research on OPIDN. Fluorinated aminophosphonates (FAP) are a group of OP compounds that were hypothesized to inhibit serine esterases through a scission in a chemically stable carbon-phosphorus bond. Through the use of surface enhanced laser desorption/absorption time of flight mass spectrometry, the FAP compounds were shown to covalently phosphorylate the active site serine of butyrylcholinesterase and subsequently age through dealkylation. To begin modeling OPIDN, correlations were found in the bimolecular rate constants of inhibition of AChE and NTE using hen brain, mouse brain, and human recombinant enzymes. Furthermore, correlations in relative inhibitory potentials were found that could predict the neuropathic potential of OP compounds. Finally, two point mutations in NTE were found in patients with a hereditary spastic paraplegia that had clinical presentations similar to OPIDN. Through site-directed mutagenesis, these mutations were created in the catalytic domain of NTE and found to have altered enzymological properties, including reduced kinetic rates of substrate hydrolysis, inhibition, and aging. This research reveals that the mechanism of inhibition by OP compounds can be elucidated using mass spectrometry. Additionally, associations of kinetic values between rodents, hens, and humans may lead to further modeling of OPIDN. In conclusion, alterations in the enzymological properties of NTE may be associated with pathology presented in patients with and associated motor neuron disease. | en_US |
dc.format.extent | 565406 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 | Neuropathy Target Esterase | en_US |
dc.subject | Organophosphorus | en_US |
dc.subject | Acetylcholinesterase | en_US |
dc.subject | Motor Neuron Disease | en_US |
dc.subject | Mass Spectrometry | en_US |
dc.title | Mechanisms of Prediction and Potential Causation of Organophosphate Induced Delayed 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 | Richardson, Rudy J. | en_US |
dc.contributor.committeemember | Hollenberg, Paul F. | en_US |
dc.contributor.committeemember | Mancuso, Peter | en_US |
dc.contributor.committeemember | Stuckey, Jeanne A. | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/63785/1/ndhein_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.