Mechanisms of Pesticide-Induced Neurobehavioral Deficits: Relevance to ADHD

描述（由申请人提供）：注意缺陷多动障碍（ADHD）是一种临床异质性障碍，以冲动、多动和注意缺陷为核心特征，估计影响全世界8-12%的学龄儿童。虽然多动症是一种复杂的疾病，有重要的遗传因素，但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-环境相互作用可能与多动症的病因有关。一些环境因素已被确定为多动症的潜在危险因素，包括产前接触酒精、烟草和铅。然而，对ADHD环境风险因素的研究一直受到阻碍，因为难以量化人类的环境暴露，以及出于伦理考虑不可能对人类进行实验暴露。为了推进这一领域的进展，当前应用程序的目标是在神经毒理学（理查森博士）、多动症遗传学（法拉恩博士）、环境流行病学和儿童健康（法拉恩博士）等专家之间建立一个“虚拟联盟”。Yolton， lanphhear和Froehlich)，以促进转化研究，探索发育性拟除虫菊酯暴露与ADHD之间的关系。这个应用程序建立在理查森博士目前的资助上，题为“农药引起的神经行为缺陷的机制：与多动症相关”。这项拨款产生的数据表明，发育过程中暴露于拟除虫菊酯类杀虫剂溴氰菊酯的小鼠产生的神经化学和行为功能障碍与多动症患者相似。此外，流行病学数据显示，儿童尿中拟除虫菊酯代谢物水平升高使儿童诊断为ADHD的风险增加2-3倍。本研究旨在确定基于发育性农药暴露的ADHD动物模型中基因表达的改变，在一个具有良好特征的ADHD患者队列样本中验证这些分子生物标志物，并在一个正在进行的前瞻性出生队列中测试农药暴露、基因表达变化和行为改变之间的关系。

DESCRIPTION (provided by applicant): Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder characterized by core features of impulsivity, hyperactivity, and attention deficits, which is estimated to affect 8-12% of school-aged children worldwide. While ADHD is a complex disorder with significant genetic contributions, 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 of ADHD. Several environmental factors have been identified as potential risk factors for ADHD, including prenatal exposure to alcohol, tobacco, and lead. However, studies of environmental risk factors for ADHD have been hindered by the difficulties of quantifying environmental exposures in humans along with the impossibility of conducting experimental exposures of humans due to ethical considerations. To advance progress in this area, the goal of the current application is to develop a "Virtual Consortium" between experts in neurotoxicology (Dr. Richardson), ADHD genetics (Dr. Faraone), and environmental epidemiology and children's health (Drs. Yolton, Lanphear and Froehlich) to promote translational research exploring the relationship between developmental pyrethroid exposure and ADHD. This application builds on Dr. Richardson's current grant entitled "Mechanisms of Pesticide-Induced Neurobehavioral Deficits: Relevance to ADHD". Data generated from this grant has demonstrated that developmental exposure of mice to the pyrethroid pesticide deltamethrin produces neurochemical and behavioral dysfunction similar to that observed in ADHD patients. Furthermore, epidemiological data reveal that elevated urinary pyrethroid metabolite levels in children increases risk of ADHD diagnosis in children 2-3 fold. This proposal seeks to identify alterations in gene expression in an animal model of ADHD based on developmental pesticide exposure, validate these molecular biomarkers in samples from a well characterized cohort of ADHD patients, and to test the association between pesticide exposure, gene expression changes, and behavioral alterations in an ongoing prospective birth cohort.