Mechanisms of Sarin Neurobehavioral Teratogenicity

沙林神经行为致畸机制

• 批准号: 7139442
• 负责人: JOSEPH YANAI
• 金额: $ 23.33万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7139442
• 关键词: Aves; behavioral /social science research tag; biological models; bioterrorism /chemical warfare; chick embryo; cholinergic agents; developmental neurobiology; domestic animals; dosage; embryo /fetus toxicology; enzyme activity; ethology; infant animal; innervation; isozymes; learning; model design /development; nerve gas; neuropsychology; neurotoxicology; nonmammalian vertebrate embryology; protein kinase C; protein transport; serotonin; teratogens

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：战争和恐怖主义中的神经气体（例如沙林）。尽管萨林在成熟的生物体中已知作为神经毒性的作用，但几乎没有关于阈值或机制的信息，它对它对更敏感的发育型大脑发挥作用，而当前的建议将建立这种影响的鸟类模型。像人类一样，雏鸡很容易受到有机磷酸盐诱导的神经病的影响，并且鸡蛋的现成可用性以及缺乏混杂的母体毒性使小鸡成为这些研究的理想模型。根据我们最近对有机磷酸盐农药的发现，我们假设在高齿肠腹膜中间部分（IMHV）中胆碱能诱导的PKCV的易位/激活是有机磷酸盐诱导的养鸡养鸡行为的特性促磷酸培养地的机制的主要成分。 PKC与印迹之间的关系将在药理研究中得到验证。 SARIN将被注入鸡蛋中，并将评估IMHV核有关的与胆碱能诱导的PKC功能以及与印迹和学习有关的胆碱能标记的孵化小鸡的印迹行为。结果将与其他神经（5-羟色胺）进行比较。特别强调的是不会引起畸形的剂量的神经染色性，以模拟显然在恐怖主义事件中可能未发现的显然无毒暴露的影响。这些发现将提供一个模型，以确定使用在实验室中已经建立的疗法以及将工作扩展到哺乳动物模型的疗法的未来研究的Sarin神经行为致畸性的机制。禽模型也可能有助于快速筛选其他神经剂的发育神经毒性。我们的具体目的是：1。建立用于沙林神经行为致病性的鸟类（雏鸡）模型。 2。检验以下假设：SARIN先进的剂量低于全身毒性阈值（在SA1中建立）会损害与​​胆碱能神经有关的行为。 3。检验以下假说：废除胆碱能诱导的PKC的易位/激活，主要是γ同工型，在IMHV中是一种主要的机制，是沙林神经行为致畸性的主要机制，并评估了这种缺陷与chosynaptic chynaptic和cholynaptic choligon cholinegrinicnicrinicnicrinegrinerinnicrinerin的关系。