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: 8720193
• 负责人: Jason R Richardson
• 金额: $ 11.9万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720193
• 关键词: Mechanisms; Pesticide; Induced; Neurobehavioral; Deficits

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）： 注意力缺陷多动障碍（ADHD）是一种临床异质性障碍，其特征在于冲动，多动和注意力缺陷的核心特征。据估计，ADHD影响8-12%的 全世界的学龄儿童。ADHD是一种复杂的疾病，具有显着的遗传贡献。 然而，没有一个单一的基因与很大比例的病例有关，这表明， 环境因素或基因-环境相互作用可能有助于病因学或临床 ADHD的表现。在ADHD患者中观察到多巴胺转运蛋白（DAT）多态性和DAT表达升高，表明DAT水平的改变可能有助于ADHD。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，在子宫内农药暴露可能有助于ADHD的发病率或严重程度。该实验室的最新数据表明，在发育期间暴露于低水平拟除虫菊酯类农药溴氰菊酯的小鼠后代表现出与ADHD儿童相似的症状，包括DAT水平升高、多动、对精神兴奋剂的反常平静反应、行为缺陷以及这些效应的男性偏好。重要的是，引起这些作用的剂量等于或低于EPA为溴氰菊酯确立的无明显不良作用水平（NOAEL）。这一点尤其值得注意，因为EPA在对农药做出监管决定时使用了NOAEL。 由于有记录表明孕妇暴露于拟除虫菊酯，并且拟除虫菊酯的使用在过去十年中急剧增加，因此将农药暴露评估为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来测试ADHD的治疗方法，并提供了对这种疾病的基本机制的深入了解。在这里，研究人员提出了三个具体目标来研究溴氰菊酯对多巴胺系统影响的潜在机制，并描述发育溴氰菊酯暴露源的行为影响。然后，研究人员将利用这些信息来利用这种新模型来确定ADHD治疗干预的分子靶点。

项目成果

Toxicokinetics and toxicodynamics of paraquat accumulation in mouse brain.

• DOI: 10.1016/j.expneurol.2008.11.003
• 发表时间: 2009-02
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Prasad, Kavita;Tarasewicz, Elizabeth;Mathew, Jason;Strickland, Pamela A. Ohman;Buckley, Brian;Richardson, Jason R.;Richfield, Eric K.
• 通讯作者: Richfield, Eric K.