Behavioral and Neurological Effects of Developmental Pyrethroid Exposure in Rodents

啮齿类动物发育拟除虫菊酯暴露的行为和神经系统影响

• 批准号: 10152656
• 负责人: James Burkett
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152656
• 关键词: Address; Agriculture; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biological; Biological Assay; Brain; Caring; Carrier Proteins; Cells; Chemicals; Child; Communication; Complex; Corpus striatum structure; Development; Development Plans; Developmental Delay Disorders; Disease; Dopamine; Dopamine D1 Receptor; Dose; Electrophysiology (science); Empathy; Environmental Risk Factor; Exposure to; Fostering; Generations; Goals; Household; Human; Insecta; Intervention; Knowledge; Link; Literature; Mental disorders; Mentors; Mentorship; Microtus; Morphology; Mus; Neurobiology; Neurologic; Neurologic Effect; Neurons; No-Observed-Adverse-Effect Level; Pair Bond; Parkinson Disease; Perinatal Exposure; Periodicity; Pesticides; Phase; Phenotype; Policies; Positioning Attribute; Pregnancy; Preventive measure; Program Development; Property; Public Health; Rattus; Regulation; Research; Research Support; Research Training; Risk; Rodent; Rodent Model; Scanning; Schizophrenia; Social Behavior; Social Interaction; Study models; Synapses; Techniques; Testing; Time; Toxic Environmental Substances; Toxicant exposure; Training; Ventral Striatum; Vertebral column; Vesicle; autism spectrum disorder; base; behavior test; behavioral phenotyping; brain behavior; career development; communication behavior; density; design; developmental disease; disorder control; disorder risk; dopamine system; dopamine transporter; epidemiology study; extracellular; innovation; morphometry; mouse model; nervous system disorder; neurochemistry; neurodevelopment; neurophysiology; neurotoxic; neurotoxicology; novel; patch clamp; prairie vole; programs; psychopathic personality; pyrethroid; repetitive behavior; social attachment; social cognition; social deficits; stress disorder; time use; trafficking

Project Summary Pesticides are biocidal, principally neurotoxic chemicals commonly used in the USA and throughout the world for agriculture, landscaping, household use, and insect-born disease control. Because many pesticides have been linked to risk for various neurological disorders, the proper determination of safe exposure levels for each pesticide is critical to public health. Recent epidemiological studies in our lab and others have linked perinatal exposure to pyrethroid pesticides with increased risk for autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) in children. Our lab has also demonstrated that mice exposed to pyrethroid concentrations below the EPA “no observable adverse effect” level have alterations in dopamine (DA) release, storage, and trafficking, as well as an ADHD-related behavioral phenotype. Critically, no existing animal study has evaluated the impact of pyrethroid exposure on social behaviors relevant to psychiatric disorders like ASD. There is a critical knowledge gap regarding the full extent of the behavioral and neurophysiological phenotypes caused by low-dose exposure to pyrethroids and relevant to ADHD and ASD risk. To address this knowledge gap, we will take advantage of the extraordinary expertise of the Miller lab in neurotoxicology, as well as my expertise in complex social behavior and the prairie vole, an animal model with unique social behaviors considered translationally relevant to ASD. We propose to study the effects of developmental pyrethroid exposure on neurophysiology and behavior in translational animal models relevant to human psychiatric disorders. In Aim 1, we will determine the behavioral phenotype of pyrethroid-exposed mice by testing for a broad range of behavioral deficits relevant to ASD, including social interaction, communication, repetitive behaviors, and the new generation of empathy-based behavioral tests. In Aim 2, we will use a wide range of morphological, neurochemical and electrophysiological techniques to determine the neurophysiological changes in DA storage and release in pyrethroid-exposed mice. In Aim 3, I will carry these same techniques into my independent research program, where I will use them to determine the critical disruptions in DAT in pyrethroid-exposed mice. In Aim 4, I will more fully develop my independent research program by determining the behavioral and neurophysiological phenotype of pyrethroid exposed prairie voles, focusing on alterations in unique social behaviors shared between human and vole, including social bonding, spontaneous parental care, and empathy-based consoling behavior. This project is designed to develop a successful long-term research program focused on the contribution of environmental toxins to risk for psychiatric disease. This will involve a substantial training and career development program led by primary mentor Dr. Gary Miller, an expert in neurotoxicology; and involving a mentoring team consisting of Dr. Shannon Gourley, an expert on animal models of psychopathy and psychiatric disease; Dr. Donald Rainnie, an expert on neurodevelopment and electrophysiology; and Dr. Michael Caudle, a toxicologist and expert on mouse models of developmental toxic exposure. In addition to their expert guidance and mentorship, Dr. Gourley will contribute her significant expertise on spine density morphometry and analysis, and Dr. Rainnie will contribute his significant expertise on whole cell patch clamp. Completion of these Aims, along with the extensive training and career development plan outlined in this proposal, will help to build an innovative, productive, and long-term research program focused on the contribution of environmental toxicants to risk for psychiatric and neurological disorders, which may inform treatments, preventive measures and regulations.

项目摘要 农药是生物杀灭剂，主要是在美国和世界各地普遍使用的神经毒性化学品 用于农业、景观美化、家庭使用和虫媒疾病控制。因为许多杀虫剂 与各种神经系统疾病的风险有关，适当确定每种疾病的安全暴露水平 杀虫剂对公众健康至关重要。我们实验室和其他实验室最近的流行病学研究表明， 暴露于拟除虫菊酯类农药，增加自闭症谱系障碍（ASD）和注意力缺陷的风险 儿童多动症（ADHD）。我们的实验室还证明了暴露于拟除虫菊酯的小鼠 低于EPA“无可观察到的不利影响”水平的浓度具有多巴胺（DA）释放的改变， 储存和运输，以及ADHD相关的行为表型。关键是，没有现有的动物研究 评估了拟除虫菊酯暴露对ASD等精神疾病相关社会行为的影响。 关于行为和神经生理表型的完整程度，存在关键的知识差距 由低剂量暴露于拟除虫菊酯引起，与ADHD和ASD风险相关。 为了解决这一知识差距，我们将利用米勒实验室的非凡专业知识， 神经毒理学，以及我在复杂的社会行为和草原田鼠，一种动物模型， 被认为与ASD相关的独特社会行为。我们建议研究 发育性拟除虫菊酯暴露对转化动物模型中神经生理学和行为的影响 人类精神疾病在目标1中，我们将确定拟除虫菊酯暴露小鼠的行为表型 通过测试与ASD相关的广泛的行为缺陷，包括社会互动，沟通， 重复行为，以及新一代的基于同理心的行为测试。在目标2中，我们将使用宽 一系列的形态学，神经化学和电生理技术，以确定 拟除虫菊酯暴露小鼠DA储存和释放的神经生理学变化。在目标3中，我将携带这些 同样的技术到我的独立研究计划，在那里我将使用它们来确定关键的 在拟除虫菊酯暴露小鼠中DAT的破坏。在目标4中，我将更充分地发展我的独立研究 通过确定拟除虫菊酯暴露草原田鼠的行为和神经生理表型， 关注人类和田鼠之间共享的独特社会行为的改变，包括社会联系， 自发的父母关怀和基于同情的安慰行为。 该项目旨在制定一个成功的长期研究计划，重点关注 环境毒素对精神疾病的风险。这将涉及大量的培训和职业生涯 由主要导师加里米勒博士领导的发展计划，神经毒理学专家; 指导小组由香农·古尔利博士组成，他是精神病动物模型专家， 精神疾病;唐纳德·雷尼博士，神经发育和电生理学专家; 毒理学家和发育毒性暴露小鼠模型专家迈克尔·考德尔说。除了 他们的专家指导和指导，Gourley博士将贡献她在脊柱密度方面的重要专业知识。 形态测量和分析，和博士Rainnie将贡献他的全细胞膜片钳的重要专业知识。 完成这些目标，沿着本文件中概述的广泛培训和职业发展计划， 建议，将有助于建立一个创新的，富有成效的，长期的研究计划，重点是 环境毒物对精神和神经系统疾病风险的贡献，这可能会提供信息 治疗、预防措施和法规。