The effects of organophosphates on anxiety-related behavior and neurodevelopment

描述（由申请人提供）：低水平有机磷农药对早期胚胎发育的神经行为和神经发育的影响知之甚少。在更多地了解早期接触有机磷的有害影响之前，不太可能遵守风险预防指南。拟议研究的长期目标是确定小剂量毒死蜱和马拉硫磷对斑马鱼胚胎大脑发育和焦虑相关行为的影响。这项研究的目的是确定在发育早期不同浓度的有机磷在多大程度上导致焦虑相关行为的改变，如对边缘的偏好和对视觉刺激的回避，并确定控制焦虑相关行为的大脑区域的神经模式缺陷。斑马鱼为这项研究提供了一个很好的模型，因为每天可以收集大量的斑马鱼，它们可以直接暴露在有机磷酸盐中，而且它们是透明的，可以很容易地识别发育过程中的大脑异常。初步数据支持的主要假设是，在胚胎早期发育期间，即使是非常低水平的有机磷农药也会减少与焦虑相关的行为，并导致神经数量、生长和模式发生变化，特别是在与这些行为相关的大脑区域，如腹侧链。这项拟议研究的基本原理是，更好地了解早期和胚胎时期接触某些有机磷酸盐对行为和神经发育的影响，有可能推动分子和遗传学研究，并改变孕妇和儿童的饮食指南和风险预防策略。该假设将以两个具体目标为指导：1)评估暴露于有机磷酸盐后焦虑相关行为发展的变化；2)鉴定有机磷暴露后大脑发育性神经模式缺陷。第一个目标将使用已经建立的高通量成像系统来执行，该系统是申请人实验室中的一种新系统，对研究焦虑相关行为很有用。第二个目标将使用共聚焦显微镜和原位杂交技术，利用斑马鱼的转基因系在早期发育的神经元中表达GFP，来创建幼虫大脑区域的三维图像。这项拟议的研究意义重大，因为它有望促进对发育早期接触有机磷酸盐的潜在风险的理解。从拟议的研究中收集的结果有能力促进害虫控制替代治疗的发展，并增加人类的饮食指南。

DESCRIPTION (provided by applicant): There is very little known about the neurobehavioral and neurodevelopmental impact of low levels of organophosphate pesticides during early embryonic development. Until more is known about the detrimental effects of early exposure to organophosphates, adherence to risk prevention guidelines are unlikely. The long- term goal of the proposed research is to determine the impact of small doses of Chlorpyrifos and Malathion on brain development and anxiety-related behavior using zebrafish embryos. The objective of the proposed research is to determine the extent to which various concentrations of organophosphates during early development cause changes in anxiety-related behaviors such as a preference to be on an edge and avoidance of a visual stimulus and to identify neural patterning defects in brain regions controlling anxiety- related behavior. Zebrafish make an excellent model for the proposed research because large numbers can be collected daily, they can be directly exposed to the organophosphates, and they are transparent, allowing for easy identification of brain abnormalities during development. The main hypothesis, supported by preliminary data, is that even very low levels of organophosphate pesticides during early embryonic development will decrease anxiety-related behavior and cause changes to occur in neural numbers, growth, and patterning, particularly in brain regions linked to these behaviors, such as the ventral habenula. The rationale for the proposed research is that a better understanding of the behavioral and neurodevelopmental impacts of early and embryonic exposure to certain organophosphates has the potential to drive molecular and genetic studies and to change dietary guidelines and risk prevention strategies for pregnant women and children. The hypothesis will be guided by two specific aims: 1) To assess changes in the development of anxiety-related behaviors after exposure to organophosphates; and 2) To identify developmental neural patterning defects in the brain after exposure to organophosphates. The first aim will be performed using an already established high-throughput imaging system that is a novel system in the applicant's laboratory and is useful for the study anxiety-related behavior. The second aim will be performed using confocal microscopy coupled with in situ hybridization to create 3-D images of larval brain regions using a transgenic line of Zebrafish that express GFP in early developing neurons. The proposed research is significant because it is expected to advance understanding of the potential risks of exposure to organophosphates early in development. The results gathered from the proposed research have the capability to promote the development of alternative treatments for pest control and to augment dietary guidelines for the human population. PUBLIC HEALTH RELEVANCE: The proposed research project encompassing examination of the effects of early organophosphate exposure on brain development and behavior is relevant to public health because it will facilitate an increase in knowledge about organophosphate pathogenesis and may lead to novel risk prevention strategies such as revised dietary guidelines. Therefore, the proposed research fits well within the scope of the NIH's mission to increase the knowledge of the impact of environmental influences in order to reduce the risk and progression of human disease and disorder.