Mechanisms of Pesticide-Induced Neurobehavioral Deficits: Relevance to ADHD

描述（由申请人提供）：注意力缺陷多动障碍（ADHD）是一种临床异质性疾病，其特征为冲动、多动和注意力缺陷的核心特征，估计影响全球8-12%的学龄儿童。虽然ADHD是一种具有显著遗传贡献的复杂疾病，但没有单一基因与显著百分比的病例相关，这表明环境因素或基因-环境相互作用可能有助于ADHD的病因。一些环境因素已被确定为ADHD的潜在危险因素，包括产前暴露于酒精，烟草和铅。然而，ADHD的环境风险因素的研究受到了阻碍，因为难以量化人类的环境暴露，沿着的是由于伦理考虑而不可能进行人类的实验暴露。为了推进这一领域的进展，当前申请的目标是在神经毒理学（Richardson博士）、ADHD遗传学（Faraone博士）以及环境流行病学和儿童健康（Yolton、Lanphear和Froehlich博士）专家之间建立一个“虚拟联盟”，以促进探索发育性拟除虫菊酯暴露与ADHD之间关系的转化研究。Richardson博士目前的资助项目名为“杀虫剂诱导的神经行为缺陷的机制：与ADHD的相关性”。该资助产生的数据表明，小鼠发育暴露于拟除虫菊酯类农药溴氰菊酯会产生与ADHD患者相似的神经化学和行为功能障碍。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会使儿童ADHD诊断风险增加2-3倍。该提案旨在确定基于发育农药暴露的ADHD动物模型中基因表达的改变，验证来自ADHD患者的良好特征队列的样本中的这些分子生物标志物，并测试农药暴露，基因表达变化和行为改变之间的关联，正在进行的前瞻性出生队列。

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.