The effects of organophosphates on anxiety-related behavior and neurodevelopment

有机磷酸酯对焦虑相关行为和神经发育的影响

• 批准号: 8391917
• 负责人: Holly Richendrfer
• 金额: $ 5.22万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391917
• 关键词: Acetylcholinesterase; Acute; Address; Adherence; Adult; Affect; Afferent Neurons; Alternative Therapies; Animal Model; Anxiety; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biological Assay; Brain; Brain region; Breathing; Cessation of life; Child; Chlorpyrifos; Chronic; Conflict (Psychology); Confocal Microscopy; Coupled; Data; Defect; Development; Diet; Disease; Dose; Effectiveness; Embryo; Embryonic Development; Environment; Environmental Impact; Ethology; Exposure to; Feeling suicidal; Goals; Growth; Guidelines; Habenula; Human; Hyperactive behavior; Image; In Situ Hybridization; Knowledge; Laboratories; Larva; Lead; Link; Malathion; Measures; Mental Depression; Mission; Modeling; Molecular Genetics; Mus; Nervous system structure; Neuraxis; Neurons; Neurotransmitters; Organophosphates; Pathogenesis; Pattern; Pest Control; Pesticides; Play; Population; Pregnancy; Pregnant Women; Prevention Guidelines; Prevention strategy; Public Health; Rattus; Research; Research Project Grants; Risk; Role; Staging; Synapses; System; Techniques; Three-Dimensional Image; Time; Toxic Environmental Substances; Transgenic Organisms; Zebrafish; alternative treatment; developmental neurobiology; human disease; in utero; neural patterning; neurobehavioral; neurobehavioral disorder; neurodevelopment; neuron development; neuronal patterning; novel; postnatal; preference; relating to nervous system; toxic organophosphate insecticide exposure; toxicant; visual stimulus

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.

描述（由申请人提供）：对于早期胚胎发育过程中低水平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酸酯的有害影响之前，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。拟议研究的目的是确定早期发育过程中不同浓度的有机磷酸酯在多大程度上导致焦虑相关行为的变化，例如倾向于处于边缘和避免视觉刺激，并识别大脑中的神经模式缺陷控制焦虑相关行为的区域。斑马鱼为拟议的研究提供了一个很好的模型，因为每天可以收集大量斑马鱼，它们可以直接暴露于有机磷酸盐，而且它们是透明的，可以轻松识别发育过程中的大脑异常。得到初步数据支持的主要假设是，即使在早期胚胎发育过程中有机磷农药含量非常低，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，特别是与这些行为相关的大脑区域。 ，例如腹侧缰核。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。该假设将遵循两个具体目标：1）评估接触有机磷酸盐后焦虑相关行为发展的变化； 2) 识别接触有机磷酸盐后大脑中的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实现，该系统是申请人实验室中的一个新颖系统，对于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结合原位杂交，使用在早期发育的神经元中表达 GFP 的转基因斑马鱼系来创建幼虫大脑区域的 3D 图像。拟议的研究意义重大，因为它有望增进对开发早期接触有机磷酸盐潜在风险的了解。从拟议的研究中收集的结果能够促进害虫控制替代疗法的开发，并增强人类的饮食指南。 公共健康相关性：拟议的研究项目包括检查早期有机磷暴露对大脑发育和行为的影响，与公共健康相关，因为它将有助于增加对有机磷发病机制的了解，并可能导致新的风险预防策略，例如修订饮食指导方针。因此，拟议的研究非常适合 NIH 的使命范围，即增加对环境影响的了解，以减少人类疾病和紊乱的风险和进展。