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: 8712483
• 负责人: Holly Richendrfer
• 金额: $ 5.7万
• 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/8712483
• 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.

描述（由申请人提供）：关于早期胚胎发育过程中低水平的有机磷酸盐农药的神经行为和神经发育影响鲜为人知。除非对早期暴露于有机磷酸盐的有害影响有更多的了解，否则不太可能遵守风险预防准则。拟议的研究的长期目标是确定小剂量的毒死rif剂量和玛拉硫磷对使用斑马鱼胚胎的脑发育和与焦虑相关的行为的影响。拟议的研究的目的是确定早期发育过程中各种浓度的有机磷酸盐导致焦虑相关行为的变化，例如偏爱偏好，避免了视觉刺激，并确定控制焦虑相关行为的大脑区域中的神经模式缺陷。斑马鱼是拟议研究的绝佳模型，因为可以每天收集大量，可以直接暴露于有机磷酸盐，并且它们是透明的，可以轻松识别发育过程中脑异常。由初步数据支持的主要假设是，即使在早期胚胎发育过程中，即使是非常低的有机磷酸盐农药也会降低与焦虑相关的行为，并导致神经数量，生长和图案发生变化，尤其是在与这些行为相关的大脑区域中，例如腹侧habenula。拟议研究的理由是，对早期和胚胎暴露于某些有机磷酸盐的行为和神经发育影响有更好的了解有可能推动分子和遗传研究，并改变对孕妇和儿童的饮食指南和预防饮食指南和风险预防策略。该假设将以两个具体的目的指导：1）评估暴露于有机磷酸盐后与焦虑相关行为发展的变化； 2）暴露于有机磷酸盐后，确定大脑中的发育神经模式缺陷。第一个目标将使用已经建立的高通量成像系统进行，该系统是申请人实验室中的新型系统，对与研究焦虑相关的行为有用。第二个目标将使用共聚焦显微镜以及原位杂交结合使用，以使用斑马鱼的转基因线来创建幼虫脑区域的3-D图像，该系在早期发育的神经元中表达GFP。拟议的研究之所以重要，是因为有望提高对发育早期暴露于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为有害生物控制的替代治疗方法的发展，并为人口增强饮食指南。