Organophosphates (OPs) pose a constant threat to human health due to their widespread use as pesticides and their potential employment in terrorist attacks. The acute toxicity of OPs has been extensively studied; however, the consequences of prolonged or repeated exposure to levels of OPs that produce no overt signs of acute toxicity are poorly understood. Further, there is clinical evidence that such low-level exposures to OPs leads to prolonged deficits in cognition, although the mechanism for this effect is unknown. One long- term goal of our laboratories is to elucidate the mechanisms responsible for the prolonged neurobehavioral deficits associated with chronic low-level OP exposures such that more effective therapeutic strategies can be developed. The results of our experiments conducted during the initial funding period established that low- level exposures to the commercial pesticide, chlorpyrifos, resulted in protracted deficits in prepulse inhibition (a model of pre-attentive processing) and spatial learning without significantly affecting locomotor function. Further, chlorpyrifos was associated with decreases in neurotrophin receptors and cholinergic proteins in brain regions that are important to cognitive function. These deficits were accompanied by decreases in axonal transport measured in sciatic nerves ex vivo. However, the molecular mechanisms for the deficits in axonal transport and the extent to which such effects on axonal transport occur in the brain are unclear. The objective of this application is to identify the mechanisms responsible for alterations in axonal transport as well as to further define the long-term effects of low-level OP exposure on cognitive function. Our central hypothesis is that OPs covalently modify key proteins that are involved in axonal transport and that such modifications compromise the function of neuronal pathways that support cognitive function. To achieve our objective, we propose three specific aims: 1) Determine the consequences of chronic low-level exposure to representative OPs on attention and cognitive flexibility, 2) Determine the consequences of chronic low-level exposure to representative OPs on axonal transport in the brain, and 3) Identify the molecular mechanisms responsible for OP-induced deficits in axonal transport. To address these aims, we will use a five choice serial reaction time task to assess sustained attention, a water maze task to measure extinction (a form of cognitive flexibility) and stereotaxic injections of traceable dextrans, immunohistochemistry, and mass spectrometry to determine OP effects on axonal transport in the brain and the consequences of its impairment. The significance of this project and its relevance to public health is that by mechanistically defining OPs based on their long-term effects on essential components of information processing in animals, we will have addressed a fundamental gap in our knowledge of how OPs likely affect humans over time. The experiments will contribute to a better understanding of the toxicity associated with a class of chemicals that continues to pose a significant environmental risk to millions of people worldwide.

Public Health Relevance

Organophosphates are highly toxic chemicals that are almost ubiquitous in our environment and, accordingly, they pose a significant health risk to millions of people worldwide. While the acute toxicity of these agents has been extensively studied, the effects of chronic low-level exposures to organophosphates (especially on cognition and the neuronal processes that support cognition) are poorly understood. The experiments proposed in this application have been designed to address these issues in the rodent model by mechanistically defining organophosphates based on their long-term effects on axonal transport (a fundamental process in neurons) and specific domains of cognitive function (i.e., attention and cognitive flexibility).

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012241-10
Application #
8369870
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kirshner, Annette G
Project Start
2003-01-01
Project End
2014-10-31
Budget Start
2012-11-01
Budget End
2014-10-31
Support Year
10
Fiscal Year
2013
Total Cost
$300,161
Indirect Cost
$84,206
Name
Georgia Regents University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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
Terry Jr, A V (2012) Functional consequences of repeated organophosphate exposure: potential non-cholinergic mechanisms. Pharmacol Ther 134:355-65
Terry Jr, A V; Beck, W D; Warner, S et al. (2012) Chronic impairments in spatial learning and memory in rats previously exposed to chlorpyrfos or diisopropylfluorophosphate. Neurotoxicol Teratol 34:1-8
Terry Jr, A V; Buccafusco, J J; Gearhart, D A et al. (2011) Repeated, intermittent exposures to diisopropylfluorophosphate in rats: protracted effects on cholinergic markers, nerve growth factor-related proteins, and cognitive function. Neuroscience 176:237-53
Terry Jr, Alvin V; Decker, Michael W (2011) Neurobiology of nAChRs and cognition: a mini review of Dr. Jerry J. Buccafusco's contributions over a 25 year career. Biochem Pharmacol 82:883-90
Terry Jr, Alvin V; Callahan, Patrick M; Hall, Brandon et al. (2011) Alzheimer's disease and age-related memory decline (preclinical). Pharmacol Biochem Behav 99:190-210
Middlemore-Risher, Mary-Louise; Adam, Bao-Ling; Lambert, Nevin A et al. (2011) Effects of chlorpyrifos and chlorpyrifos-oxon on the dynamics and movement of mitochondria in rat cortical neurons. J Pharmacol Exp Ther 339:341-9
Wilson, Christina; Terry Jr, Alvin V (2010) Neurodevelopmental animal models of schizophrenia: role in novel drug discovery and development. Clin Schizophr Relat Psychoses 4:124-37

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