Organophosphorus (OP) insecticides are heavily employed in agricultural and residential uses, and have ample opportunity to expose infants and children from food and houses during critical times of their nervous system development. The mechanism of toxicity, inhibition of acetylcholinesterase (AChE), causes hyperactivity in cholinergic pathways, which can elicit compensatory neurochemical mechanisms to modulate the enhanced activity. AChE inhibition is considerably more persistent for the diethyl OP compounds than for the dimethyl OP compounds, leading to greater fluctuations in AChE activity following exposure to a dimethyl insecticide, such as methyl parathion, than to a diethyl insecticide, such as chlorpyrifos. Our preliminary results in rats have indicated more persistent whole brain muscarinic acetylcholine receptor (mAChR) decreases following early postnatal exposures to chlorpyrifos than to methyl parathion. Developmental exposures to OP insecticides cause behavioral deficits. Our preliminary results have indicated decreases in open field activity occurring only after, not during, chlorpyrifos exposures, suggesting possible permanent behavioral deficits from developmental exposures. The biochemical lesion occurs in both the central and peripheral nervous systems because of the distribution of AChE in both, so both central and peripheral effects could contribute to behavioral deficits. The possibility of permanent behavioral defects from the extended neurochemical alterations following AChE inhibition of diethyl OP insecticides has generated the following hypothesis for this project: Neurochemical aberrations and behavioral deficits will be more severe and long lasting from the more persistent phosphorylation of a diethyl OP insecticide (chlorpyrifos) during development than from a dimethyl OP insecticide (methyl parathion). The cholinergic parameters to be studied include: AChE, mAChR (total and surface), choline acetyltransferase, high affinity choline uptake, and adenylyl cyclase in brain regions, and AChE in peripheral tissues. The behavioral parameters to be studied include: developmental markers, surface righting, negative geotaxis, free-fall righting, locomotor activity, rotarod performance, grip strength, and memory and learning in two types of water mazes. The results will indicate whether certain OP insecticide chemistries elicit greater harm to the developing nervous system and whether children are likely to suffer from permanent harm to behavior, including cognition, from developmental exposures to OP insecticides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010386-04
Application #
6748968
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Kirshner, Annette G
Project Start
2001-06-01
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$243,965
Indirect Cost
Name
Mississippi State University
Department
Public Health & Prev Medicine
Type
Schools of Veterinary Medicine
DUNS #
075461814
City
Mississippi State
State
MS
Country
United States
Zip Code
39762
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Carr, Russell L; Borazjani, Abdolsamad; Ross, Matthew K (2011) Effect of developmental chlorpyrifos exposure, on endocannabinoid metabolizing enzymes, in the brain of juvenile rats. Toxicol Sci 122:112-20
Eells, Jeffrey B; Brown, Timothy (2009) Repeated developmental exposure to chlorpyrifos and methyl parathion causes persistent alterations in nicotinic acetylcholine subunit mRNA expression with chlorpyrifos altering dopamine metabolite levels. Neurotoxicol Teratol 31:98-103
Johnson, Frank O; Chambers, Janice E; Nail, Carole A et al. (2009) Developmental chlorpyrifos and methyl parathion exposure alters radial-arm maze performance in juvenile and adult rats. Toxicol Sci 109:132-42
Carr, Russell L; Nail, Carole A (2008) Effect of different administration paradigms on cholinesterase inhibition following repeated chlorpyrifos exposure in late preweanling rats. Toxicol Sci 106:186-92
Guo-Ross, Shirley X; Chambers, Janice E; Meek, Edward C et al. (2007) Altered muscarinic acetylcholine receptor subtype binding in neonatal rat brain following exposure to chlorpyrifos or methyl parathion. Toxicol Sci 100:118-27
Richardson, Jason R; Chambers, Janice E (2005) Effects of repeated oral postnatal exposure to chlorpyrifos on cholinergic neurochemistry in developing rats. Toxicol Sci 84:352-9
Betancourt, Angela M; Carr, Russell L (2004) The effect of chlorpyrifos and chlorpyrifos-oxon on brain cholinesterase, muscarinic receptor binding, and neurotrophin levels in rats following early postnatal exposure. Toxicol Sci 77:63-71
Richardson, Jason R; Chambers, Janice E (2004) Neurochemical effects of repeated gestational exposure to chlorpyrifos in developing rats. Toxicol Sci 77:83-90