The exposure to toxic organophosphate (OP) insecticides and chemical warfare agents continues to endanger many of the world's population. One potentially dire consequence of such exposure is the prolonged impairment of cognitive function. Mechanistic studies of OPs to date have focused primarily the effects of overtly toxic doses, however, little is known about the cellular and behavioral consequences of repeated exposure to doses of these agents that produce no overt signs of acute toxicity (i.e., subthreshold doses). This issue is very important since detectible levels of OPs can remain in the environment for extended periods. Accordingly, our long-term goal is further elucidate OP mechanisms such that more effective therapeutic strategies can be developed for patients suffering from exposure. The objective of this application is to identify specific relationships between cellular and biochemical manifestations of repeated, subthreshold exposures to OPs and cognitive function in an experimental animal model. We have compelling preliminary evidence from rat studies suggesting that one mechanism underlying memory dysfunction associated with repeated, subthreshold OP exposure is the impairment of fast axonal transport resulting from interactions with the motor protein, kinesin. Since axonal transport plays such a fundamental role in neuronal function, and since the cholinergic system in the brain is so important for cognitive processes, we have developed the hypothesis that the compromise of fast axonal transport by OPs, over time, leads to deficiencies in the expression of cholinergic macromolecules in sensitive regions of the brain that result in the impairment of memory function. The rationale for the proposed research is that a clear understanding of the mechanisms underlying the cognitive effects of subthreshold exposures to OPs will help us in designing treatments to reverse the effects of these agents. To test the hypothesis we propose two specific aims: 1): To evaluate the residual behavioral manifestations (especially cognitive effects) of repeated, subthreshold, exposures to both neurotoxic and non-neurotoxic OPs in an experimental animal model. 2): To identify specific relationships between OP-induced cognitive changes and impairments in fast axonal transport. We will use a water maze task to measure spatial learning, an 8-arm radial arm maze task to assess working memory, and a microtubule motility assay and video enhanced-differential interference contrast microscopy to study OP effects on kinesin and axonal transport, respectively. Immunoblotting methods and receptor autoradiography will be used to measure OP effects on the expression of key cholinergic markers in the brain, and organotypic culture methods will be employed to measure toxicity of OPs to the hippocampus. At the completion of this research we expect to identify temporal cellular changes resulting from repeated, subthreshold exposures to two representative OPs (DFP and chlorpyrifos) and their correlation with cognitive changes. These studies are significant because they will contribute to a better understanding of the toxicity associated with a class of agents that continues to pose a significant environmental risk to millions of people worldwide. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES012241-01A1
Application #
6730222
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Kirshner, Annette G
Project Start
2003-12-15
Project End
2007-11-30
Budget Start
2003-12-15
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$286,396
Indirect Cost
Name
University of Georgia
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Naughton, Sean X; Terry Jr, Alvin V (2018) Neurotoxicity in acute and repeated organophosphate exposure. Toxicology 408:101-112
Zhang, Maoxiang; Davis, Jason E; Li, Chunman et al. (2016) GGA3 Interacts with a G Protein-Coupled Receptor and Modulates Its Cell Surface Export. Mol Cell Biol 36:1152-63
Gao, Jie; Naughton, Sean X; Wulff, Heike et al. (2016) Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons. J Pharmacol Exp Ther 356:645-55
Terry Jr, Alvin V; Callahan, Patrick M; Hernandez, Caterina M (2015) Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders. Biochem Pharmacol 97:388-398
Chatzidaki, Anna; Millar, Neil S (2015) Allosteric modulation of nicotinic acetylcholine receptors. Biochem Pharmacol 97:408-417
Terry Jr, Alvin V; Callahan, Patrick M; Beck, Wayne D et al. (2014) Repeated exposures to diisopropylfluorophosphate result in impairments of sustained attention and persistent alterations of inhibitory response control in rats. Neurotoxicol Teratol 44:18-29
Wilson, Christina A; Terry Jr, Alvin V (2013) Variable maternal stress in rats alters locomotor activity, social behavior, and recognition memory in the adult offspring. Pharmacol Biochem Behav 104:47-61
Wilson, Christina A; Vazdarjanova, Almira; Terry Jr, Alvin V (2013) Exposure to variable prenatal stress in rats: effects on anxiety-related behaviors, innate and contextual fear, and fear extinction. Behav Brain Res 238:279-88
Wilson, C A; Schade, R; Terry Jr, A V (2012) Variable prenatal stress results in impairments of sustained attention and inhibitory response control in a 5-choice serial reaction time task in rats. Neuroscience 218:126-37
Terry Jr, A V (2012) Functional consequences of repeated organophosphate exposure: potential non-cholinergic mechanisms. Pharmacol Ther 134:355-65

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