The effects of organophosphates on anxiety-related behavior and neurodevelopment

描述(由申请人提供)：在早期胚胎发育过程中，低水平的有机磷农药对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。这项拟议研究的长期目标是利用斑马鱼胚胎确定小剂量毒死蜱和马拉硫磷对大脑发育和焦虑相关行为的影响。这项拟议的研究的目的是确定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变化，如偏爱处于边缘和避免视觉刺激，并确定控制焦虑相关行为的大脑区域的神经模式缺陷。对于拟议的研究来说，斑马鱼是一个很好的模型，因为每天可以收集大量斑马鱼，它们可以直接暴露在有机磷中，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，在胚胎发育早期，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，并导致神经细胞数量、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，如腹侧缰核。这项拟议研究的基本原理是，更好地了解早期和胚胎接触某些有机磷对行为和神经发育的影响，有可能推动分子和遗传研究，并改变孕妇和儿童的饮食指南和风险预防策略。该假说将以两个具体目标为指导：1)评估暴露于有机磷后焦虑相关行为的发展变化；2)确定暴露于有机磷后大脑发育中的神经模式缺陷。第一个目标将使用已经建立的高通量成像系统来实现，这是申请者实验室中的一个新系统，对学习焦虑相关行为有用。第二个目标将使用共聚焦显微镜和原位杂交相结合的方法，使用在早期发育的神经元中表达GFP的转基因斑马鱼来创建幼虫大脑区域的3D图像。这项拟议的研究意义重大，因为它有望促进人们对发育早期接触有机磷的潜在风险的理解。从拟议的研究中收集的结果有能力促进虫害防治替代疗法的开发，并增强人类人口的饮食指南。 与公共健康相关：拟议的研究项目包括研究早期接触有机磷对大脑发育和行为的影响，这与公共健康相关，因为它将促进对有机磷发病机制的了解，并可能导致新的风险预防策略，如修订饮食指南。因此，这项拟议的研究完全符合美国国立卫生研究院的使命，即增加对环境影响的影响的知识，以减少人类疾病和紊乱的风险和进展。

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.