Developmental Pyrethroid Exposure and ADHD

发育性拟除虫菊酯暴露和多动症

• 批准号: 7126469
• 负责人: Jason R Richardson
• 金额: $ 15.18万
• 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: 2005
• 资助国家: 美国
• 起止时间: 2005-09-26 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126469
• 关键词: animal breeding; attention; attention deficit disorder; behavioral /social science research tag; behavioral genetics; developmental neurobiology; dopamine transporter; early experience; environmental exposure; ethology; gene environment interaction; gene expression; gene expression profiling; laboratory mouse; longitudinal animal study; neurochemistry; neurotransmitter transport; protein metabolism; psychomotor function; pyrethroid; short term memory

DESCRIPTION (provided by applicant): Attention deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder characterized by marked impulsivity, hyperactivity, and impaired working memory. ADHD is estimated to affect 3-7% of school-age individuals in the United States alone, with a significant percentage of these cases persisting through adulthood. Although the pathophysiology of ADHD is not completely understood, disruption of the dopamine system appears to play a central role. Specifically, polymorphisms and elevated levels of the dopamine transporter (DAT) have been found in both adolescents and adults with ADHD. Elevated DAT levels are also found in the spontaneously-hypertensive rat, a well characterized animal model of ADHD. The primary medications utilized in the treatment of ADHD, methylphenidate and amphetamine, produce much of their therapeutic effects through blockade of DAT. Thus, alteration of DAT levels or function significantly contributes to the behavioral abnormalities and treatment of ADHD. Although genetic factors account for a large percentage of ADHD, an estimated 20-40% of cases do not appear to have a primary genetic etiology, suggesting that environmental factors may contribute to ADHD. Accordingly, exposure to environmental agents that alter the proper development of the dopaminergic system and enhance DAT levels may contribute to development of behaviors associated with ADHD. Our laboratory and others have demonstrated that repeated exposure of adult mice to the pyrethroid pesticide, deltamethrin, increases striatal DAT levels. We now have evidence that gestational and lactational exposure of mice to deltamethrin, at doses 4 to 40-fold below the developmental no-observable adverse effect level (NOAEL), causes longterm up-regulation of DAT and hyperactivity in adolescent mice. Therefore, the purpose of this proposal is to determine the effects of developmental pyrethroid exposure on the dopamine system and whether alterations of the dopamine system result in a behavioral phenotype similar to that of 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，其特征是明显的冲动、多动和工作记忆受损。据估计，仅在美国就有 3-7% 的学龄儿童患有 ADHD，其中很大一部分病例一直持续到成年。尽管多动症的病理生理学尚未完全了解，但多巴胺系统的破坏似乎起着核心作用。具体来说，在患有 ADHD 的青少年和成人中都发现了多态性和多巴胺转运蛋白 (DAT) 水平升高。在自发性高血压大鼠中也发现了 DAT 水平升高，这是一种经过充分表征的 ADHD 动物模型。用于治疗 ADHD 的主要药物是哌醋甲酯和安非他明，它们的大部分治疗效果是通过阻断 DAT 产生的。因此，DAT 水平或功能的改变显着有助于行为异常和 ADHD 的治疗。尽管遗传因素在 ADHD 中占很大比例，但估计 20-40% 的病例似乎没有主要的遗传病因，这表明环境因素可能会导致 ADHD。因此，接触改变多巴胺能系统正常发育并提高 DAT 水平的环境因素可能会导致与 ADHD 相关的行为的发展。我们的实验室和其他实验室已经证明，成年小鼠反复接触拟除虫菊酯杀虫剂溴氰菊酯会增加纹状体 DAT 水平。我们现在有证据表明，妊娠期和哺乳期小鼠接触溴氰菊酯，剂量低于发育中不可观察到的不良反应水平 (NOAEL) 4 至 40 倍，会导致青少年小鼠 DAT 长期上调和过度活跃。因此，本提案的目的是确定发育期拟除虫菊酯暴露对多巴胺系统的影响，以及多巴胺系统的改变是否会导致与 ADHD 类似的行为表型。