Mechanisms of Pesticide-Induced Neurobehavioral Deficits: Relevance to ADHD

农药引起的神经行为缺陷的机制：与多动症的相关性

基本信息

批准号：
7337586
负责人：
Jason R Richardson
金额：
$ 55.77万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7337586
关键词：
Adverse effects Affect Amphetamines Animal Model Attention Attention deficit hyperactivity disorder Behavior Behavioral Behavioral Paradigm Child Clinical Complement Complex Data Development Disease Dopaminergic Cell Dose Embryo Environmental Risk Factor Etiology Exhibits Female Functional disorder Gender Genes Genetic Genetic Polymorphism Hyperactive behavior Impulsivity Incidence Laboratories Lead Link Mediating Methylphenidate Modeling Molecular Molecular Target Mus Neurons Nuclear Outcome Patients Pesticides Pregnant Women RNA Interference Research Personnel Risk Factors Role School-Age Population Severities Sex Characteristics Signal Transduction Symptoms Techniques Testing Therapeutic Agents Therapeutic Intervention United States Environmental Protection Agency Viral decamethrin dopamine system dopamine transporter gender preference gene environment interaction improved in utero in vivo insight male neurobehavioral neurochemistry novel pesticide exposure programs psychostimulant pyrethroid response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder characterized by core features of impulsivity, hyperactivity, and attention deficits. ADHD is estimated to affect 8-12% of school-aged children worldwide. ADHD is a complex disorder with significant genetic contributions. However, no single gene has been linked to a significant percentage of cases, suggesting that environmental factors or gene-environment interactions may contribute to the etiology or clinical manifestation of ADHD. Dopamine transporter (DAT) polymorphisms and elevated expression of the DAT have been observed in ADHD patients, suggesting alterations in DAT levels may contribute to ADHD. Since environmental factors, such as pesticides, have been shown to alter DAT expression, we have hypothesized that in utero pesticide exposure may contribute to the incidence or severity of ADHD. Recent data from this laboratory have demonstrated that the offspring of mice exposed to low levels of the pyrethroid pesticide deltamethrin during development exhibit similar symptoms as observed in children with ADHD, including elevated DAT levels, hyperactivity, a paradoxical calming response to psychostimulants, behavioral deficits, and a male gender-preference of these effects. Importantly, the doses that elicited these effects were at or below the no observable adverse effect level (NOAEL) established by the EPA for deltamethrin. This is particularly notable because the NOAEL used by the EPA when making regulatory decisions on pesticides. Because there has been documented exposure of pregnant women to pyrethroids and pyrethroid use has increased dramatically in the last decade, it may be prudent to evaluate pesticide exposure as a potential risk factor for ADHD. Furthermore, these mice represent a novel animal model to test therapies for ADHD and provide insight into the basic mechanisms underlying this disorder. Here, the investigators propose three Specific Aims to investigate mechanisms underlying the effects of deltamethrin on the dopamine system and characterize the behavioral effects of developmental deltamethrin expsoure. The investigators will then use this information to exploit this novel model to identify molecular targets for therapeutic intervention in ADHD.

描述（由申请人提供）：注意缺陷多动症（ADHD）是一种临床上异质性疾病，其特征是冲动性，多动症和注意力缺陷的核心特征。估计多动症会影响8-12％全球学龄儿童。 ADHD是一种具有重要遗传贡献的复杂疾病。但是，尚无单一基因与大量病例有关，表明环境因素或基因环境相互作用可能有助于病因或临床多动症的表现。多巴胺转运蛋白（DAT）多态性和DAT的表达升高在ADHD患者中，表明DAT级别的改变可能会导致多动症。由于已经证明环境因素（例如农药）会改变DAT表达，因此我们假设在子宫内，农药暴露可能有助于多动症的发病率或严重性。该实验室的最新数据表明，发育过程中暴露于拟除虫菊酯农药三甲蛋白的小鼠的后代表现出与ADHD儿童相似的症状，包括DAT水平升高，多动症，对精神匹配剂，行为缺陷，行为缺陷，男性性别差异的矛盾平静反应。重要的是，引起这些作用的剂量在EPA为Deltamethrin建立的无观察不良效应水平（NOAEL）下方。这尤其值得注意，因为EPA在制定农药的监管决定时使用的NOAEL。由于孕妇暴露于拟除虫菊酯和拟除虫菊酯的使用情况下，在过去的十年中使用了急剧增加，因此将农药暴露作为多动症的潜在危险因素可能是审慎的。此外，这些小鼠代表了一种新型的动物模型，用于测试多动症的疗法，并洞悉该疾病的基本机制。在这里，研究人员提出了三个具体旨在研究三分之一对多巴胺系统影响的机制，并表征了发育二甲素体验的行为效应。然后，研究人员将使用此信息来利用这种新型模型来识别ADHD治疗干预的分子靶标。