Behavioral and Neurological Effects of Developmental Pyrethroid Exposure in Rodents

项目摘要 杀虫剂是生物杀伤性的，主要是在美国和世界各地普遍使用的神经毒性化学物质。 用于农业、园林绿化、家庭使用和昆虫传播疾病控制。因为很多农药都有 与各种神经疾病的风险有关，正确确定每种疾病的安全暴露水平 农药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，围产期 接触拟除虫菊酯类农药会增加患自闭症谱系障碍(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，接触拟除虫菊酯的小鼠 低于EPA“无明显副作用”的浓度会改变多巴胺(DA)的释放， 储存和贩卖，以及与ADHD相关的行为表型。关键的是，没有现有的动物研究 评估了拟除虫菊酯暴露对与自闭症等精神障碍相关的社会行为的影响。 关于行为和神经生理表型的全面程度，存在严重的知识差距 由低剂量的拟除虫菊酯引起，与ADHD和ASD的风险有关。 为了解决这一知识差距，我们将利用米勒实验室在 神经毒理学，以及我在复杂社会行为和草原田鼠方面的专业知识，一个具有 独特的社会行为被认为与ASD有翻译上的相关性。我们建议研究 拟除虫菊酯对拟除虫菊酯动物模型神经生理和行为的影响 人类精神障碍。在目标1中，我们将确定拟除虫菊酯暴露小鼠的行为表型。 通过测试与自闭症相关的广泛行为缺陷，包括社交、沟通、 重复性行为，以及新一代基于同理心的行为测试。在目标2中，我们将使用广泛的 一系列的形态、神经化学和电生理技术来确定 拟除虫菊酯暴露小鼠多巴胺储存和释放的神经生理学变化。在《目标3》中，我将携带这些 同样的技术应用到我的独立研究项目中，我将使用它们来确定关键的 拟除虫菊酯暴露小鼠的DAT中断。在目标4中，我将更充分地发展我的独立研究 通过测定拟除虫菊酯暴露的草原田鼠的行为和神经生理表型， 专注于人类和田鼠之间共享的独特社会行为的变化，包括社会纽带， 自发的父母关爱和基于同理心的安慰行为。 该项目旨在制定一项成功的长期研究计划，重点是 环境毒素有可能引发精神疾病。这将涉及大量的培训和职业生涯。 由初级导师、神经毒理学专家加里·米勒博士领导的发展计划； 由精神病动物模型专家香农·古利博士组成的指导团队 精神疾病专家唐纳德·雷尼博士，神经发育和电生理学专家； 毒物学家和发育毒性暴露小鼠模型的专家迈克尔·考德尔说。除了……之外 在他们的专家指导和指导下，Gourley博士将贡献她在脊柱密度方面的重要专业知识 Rainnie博士将贡献他在全细胞膜片钳方面的重要专业知识。 完成这些目标，以及本文件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、多产的和长期的研究计划，专注于 环境毒物对精神和神经疾病风险的贡献，这可能有助于 治疗、预防措施和法规。

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.