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

• 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
• 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

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)： 注意缺陷多动障碍(ADHD)是一种以冲动、多动和注意缺陷为核心特征的临床异质性障碍。据估计，8%-12%的人患有ADHD 世界各地的学龄儿童。ADHD是一种复杂的疾病，有显著的遗传因素。 然而，没有单个基因与很大比例的病例有关，这表明 环境因素或基因-环境相互作用可能在病因或临床上起作用。 注意缺陷多动障碍的表现。在ADHD患者中观察到多巴胺转运体(DAT)基因多态性和DAT表达升高，提示DAT水平的改变可能参与了ADHD的发病。由于环境因素，如农药，已被证明可以改变DAT的表达，我们假设在子宫内接触农药可能会导致ADHD的发生或严重程度。该实验室的最新数据表明，在发育过程中暴露于低水平拟除虫菊酯杀虫剂溴氰菊酯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、对精神刺激剂的矛盾镇静反应、行为缺陷以及这些影响的男性性别偏好。重要的是，引起这些影响的剂量等于或低于美国环保局为溴氰菊酯设定的无可观察到的不良影响水平(NOAEL)。这一点尤其值得注意，因为环保局在做出农药监管决定时使用了NOAEL。由于有记录表明孕妇接触拟除虫菊酯，而且在过去十年中拟除虫菊酯使用量大幅增加，因此评估农药暴露作为ADHD的潜在风险因素可能是谨慎的。此外，这些小鼠代表了一种新的动物模型，可以测试ADHD的治疗方法，并提供对这种疾病潜在的基本机制的洞察。在这里，研究人员提出了三个具体目标，以调查溴氰菊酯对多巴胺系统影响的潜在机制，并表征发育过程中溴氰菊酯的行为影响。然后，研究人员将利用这一信息来开发这一新模型，以确定ADHD治疗干预的分子靶点。