Modeling Developmental Neurotoxicity of Pesticides in Zebrafish

农药对斑马鱼发育神经毒性的建模

• 批准号: 8059851
• 负责人: LORI A WHITE
• 金额: $ 15.34万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-10 至 2011-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059851
• 关键词: Adverse effects; Affect; Agriculture; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biological Models; Brain; Child; Data; Development; Diagnosis; Dopamine; Dose; Embryo; Epidemiology; Exhibits; Exposure to; Functional disorder; Gene Expression; Genetic; Goals; Household; Hyperactive behavior; Laboratories; Late Effects; Lead; Mammals; Measurable; Methylphenidate; Modeling; Molecular; Mus; Nervous system structure; Organophosphates; Pesticides; Phase; Physiological; Population; Pregnant Women; Preschool Child; Public Health; Reporting; Risk; Ritalin; Screening procedure; Signal Transduction; Study models; Symptoms; Therapeutic; Time; United States; United States National Center for Health Statistics; Urine; Zebrafish; aged; decamethrin; developmental neurotoxicity; dopamine system; dopamine transporter; gender preference; high throughput screening; human data; insight; male; mouse model; neurochemistry; novel; pesticide poisoning; pyrethroid

Pyrethroid pesticides are the predominant pesticide for household use along with their uses in agriculture and public health. Significant levels of pyrethroid metabolites have been found in the urine of pregnant women and in preschool children. This raises concern that developmental exposure to pyrethroids may cause damage to the developing nervous system. Recent data from the Richardson laboratory demonstrate that mice developmentally exposed to low levels of the pyrethroid pesticide deltamethrin exhibit symptoms similar to those observed in children with Attention Deficit Hyperactivity Disorder (ADHD), including elevated dopamine transporter (DAT) levels, hyperactivity and impulsive-like behavior, amelioration of the behavioral deficits by methylphenidate (Ritalin), 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. Furthermore, we now have epidemiological evidence that children with measurable levels of a deltamethrin metabolite in their urine are more than twice as likely to be diagnosed with ADHD. Therefore, it is imperative to determine whether pyrethroid pesticides other than deltamethrin cause similar effects and the mechanism(s) by which pyrethroids alter the developing brain. There are currently 16 pyrethroid pesticides registered for use in the United States and examination of the developmental effects of these compounds using the mouse model would be prohibitively expensive and time-consuming. We propose to use the zebrafish (Danio rerio) as a model to assess the risk of developmental exposure to pyrethroid pesticides and to investigate the mechanisms of pyrethroid alterations in dopamine signaling. The zebrafish model system is ideal for these studies as they exhibit significant genetic and physiological similarity to mammals, are suited for moderate to high-throughput screening, and allow for direct exposure of the embryo. Our data demonstrate that developmental exposure to deltamethrin has similar effects in zebrafish as observed in the mouse model, including increased expression of the DAT, and increased activity. Our preliminary data also demonstrate that the effects of pyrethroids on the developing embryo differ between various pyrethroids. Here, we propose 3 Specific Aims to characterize the neurochemical and behavioral effects of developmental pyrethroid exposure, determine molecular mechanisms by which pyrethroids affect the dopamine system, and to screen other pyrethroids for their ability to reproduce these effects. These studies will provide insight into mechanisms by which developmental pyrethroid exposure alters the dopamine system and how these alterations lead to behavioral dysfunction. Development of a zebrafish model of ADHD would allow for high-throughput studies to screen for pesticide toxicity, explore ADHD pathophysiology in addition to screening for therapeutic compounds to treat ADHD.

拟除虫菊酯农药是家庭使用及其农业用途的主要农药 和公共卫生。孕妇尿液中发现大量拟除虫菊酯代谢物 妇女和学龄前儿童。这引起了人们的关注，即发育期接触拟除虫菊酯可能会 对发育中的神经系统造成损害。理查森实验室的最新数据 证明小鼠在发育过程中接触低水平的拟除虫菊酯农药溴氰菊酯 表现出与注意力缺陷多动障碍儿童相似的症状 （ADHD），包括多巴胺转运蛋白（DAT）水平升高、多动和冲动行为， 哌甲酯（利他林）改善行为缺陷，以及男性性别偏好 这些影响。重要的是，引起这些影响的剂量等于或低于未观察到的剂量 EPA 制定的溴氰菊酯不良反应水平 (NOAEL)。此外，我们现在有 流行病学证据表明，儿童尿液中含有可测量水平的溴氰菊酯代谢物 被诊断患有多动症的可能性是其两倍多。因此，必须确定 除溴氰菊酯以外的拟除虫菊酯类农药是否会产生类似的效果及其机制 拟除虫菊酯会改变发育中的大脑。目前已有16种拟除虫菊酯类农药登记 在美国的使用并使用以下方法检查这些化合物的发育影响 小鼠模型将非常昂贵且耗时。我们建议使用斑马鱼 （Danio rerio）作为评估拟除虫菊酯类杀虫剂发育暴露风险的模型 研究拟除虫菊酯改变多巴胺信号传导的机制。斑马鱼模型系统 是这些研究的理想选择，因为它们与哺乳动物表现出显着的遗传和生理相似性， 适用于中等到高通量筛选，并允许直接暴露胚胎。我们的数据 证明在发育过程中接触溴氰菊酯对斑马鱼具有与观察到的相似的影响 小鼠模型，包括 DAT 表达增加和活性增加。我们的初步 数据还表明，拟除虫菊酯对发育中的胚胎的影响因不同种类而异。 拟除虫菊酯。在这里，我们提出了 3 个具体目标来表征神经化学和行为效应 发育拟除虫菊酯暴露，确定拟除虫菊酯影响发育的分子机制 多巴胺系统，并筛选其他拟除虫菊酯重现这些作用的能力。这些 研究将深入了解发育性拟除虫菊酯暴露改变的机制 多巴胺系统以及这些改变如何导致行为功能障碍。斑马鱼的发育 ADHD 模型将允许进行高通量研究来筛选农药毒性，探索 ADHD 除了筛选治疗多动症的治疗化合物外，还进行病理生理学研究。