Nerve gases such as sarin are used in warfare and terrorism. Despite sarin's known role as a neurotoxicant in the mature organism, there is almost no information on the thresholds or mechanisms by which it exerts its effects on the more sensitive developing brain, and the current proposal will establish an avian model for such effects. Chicks, like humans, are vulnerable to organophosphate-induced neuropathies and the ready availability of chick eggs and the absence of confounding maternal toxicity make the chick an ideal model for these studies. Based on our recent findings with organophosphate pesticides, we hypothesize that a defect in the cholinergic-induced translocation/activation of PKCv in the intermedial part of the hyperstriatum ventrale (IMHV) is a major component in the mechanisms of the organophosphate-induced teratogenicity of imprinting behavior in the chick. The relationship between PKC and imprinting will be verified in a pharmacological study. Sarin will be injected into chicken eggs and the IMHV nucleus-related imprinting behavior of the hatching chicks will be evaluated, along with cholinergic-induced PKC function and cholinergic markers related to imprinting and learning. The results will be compared to an additional innervation (serotonin). Special emphasis will be placed on neuroteratogenicity at doses that do not cause malformation so as to model the effects of apparently subtoxic exposures that might otherwise go undetected in a terrorist incident. The findings will provide a model for ascertaining the mechanism of sarin neurobehavioral teratogenicity for future studies on the reversal of the defects using therapies already established in our laboratories, and for extension of the work to mammalian models. The avian model may also be useful for rapid screening of developmental neurotoxicity of other nerve agents.
Our specific aims are: 1. To establish an avian (chick) model for sarin neurobehavioral teratogenicity. 2. To test the hypothesis that sarin prehatch administration in doses below the systemic toxicity threshold (established in SA1) impairs behaviors related to cholinergic innervation. 3. To test the hypothesis that abolition of the cholinergic-induced translocation/activation of PKC, mainly the gamma isoform, in the IMHV is a major mechanisms underlying the neurobehavioral teratogenicity of sarin, and to assess the relationship of this defect to presynaptic and postsynaptic cholinergic function upstream from PKC, comparison to serotonin. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES014358-02
Application #
7270101
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Kirshner, Annette G
Project Start
2006-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$189,345
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Dotan, Sharon; Pinkas, Adi; Slotkin, Theodore A et al. (2010) An avian model for the reversal of neurobehavioral teratogenicity with neural stem cells. Neurotoxicol Teratol 32:481-8
Yanai, Joseph; Brick-Turin, Yael; Dotan, Sharon et al. (2010) A mechanism-based complementary screening approach for the amelioration and reversal of neurobehavioral teratogenicity. Neurotoxicol Teratol 32:109-13
Pinkas, Adi; Slotkin, Theodore A; Brick-Turin, Yael et al. (2010) Neurobehavioral teratogenicity of perfluorinated alkyls in an avian model. Neurotoxicol Teratol 32:182-6
Yanai, Joseph; Pinkas, Adi; Seidler, Frederic J et al. (2009) Neurobehavioral teratogenicity of sarin in an avian model. Neurotoxicol Teratol 31:406-12
Billauer-Haimovitch, Hana; Slotkin, Theodore A; Dotan, Sharon et al. (2009) Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by nicotine administration and neural stem cell transplantation. Behav Brain Res 205:499-504
Slotkin, Theodore A; Seidler, Frederic J; Ryde, Ian T et al. (2008) Developmental neurotoxic effects of chlorpyrifos on acetylcholine and serotonin pathways in an avian model. Neurotoxicol Teratol 30:433-9
Yanai, Joseph; Dotan, Sharon; Goz, Roman et al. (2008) Exposure of developing chicks to perfluorooctanoic acid induces defects in prehatch and early posthatch development. J Toxicol Environ Health A 71:131-3