Neurotoxicology of deltamethrin in the developing brain

发育中大脑中溴氰菊酯的神经毒理学

• 批准号: 10271267
• 负责人: Thomas Arthur Green
• 金额: $ 48.69万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-28 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271267
• 关键词: Action Potentials; Affect; Agriculture; Animal Model; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Brain; Brain region; Categories; Cells; Complement; Corpus striatum structure; Deterioration; Development; Dopamine; Electrophysiology (science); Environmental Exposure; Exposure to; Functional disorder; Gas Chromatography; General Population; Guidelines; Household; Human; Hyperactivity; Image; Immunohistochemistry; Impulsivity; Injections; Insecta; Interneuron function; Interneurons; Lactation; Life; Lifestyle-related condition; Mammals; Mass Fragmentography; Mass Spectrum Analysis; Methods; Modeling; Molecular; Motor Activity; Mus; Neurodevelopmental Disorder; Neurons; Neurotoxins; No-Observed-Adverse-Effect Level; Nucleus Accumbens; Outcome Study; Output; Parvalbumins; Pathway interactions; Pattern; Pesticides; Pregnancy; Preparation; Process; Property; Protein Isoforms; Proteins; Reporting; Risk; Risk Factors; Rodent Model; Schools; Signal Transduction; Slice; Social Behavior; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Synapses; Testing; Toxic Environmental Substances; Toxic effect; United States Environmental Protection Agency; Viral Vector; autism spectrum disorder; base; behavioral phenotyping; behavioral study; brain tissue; cell type; course development; cross reactivity; decamethrin; designer receptors exclusively activated by designer drugs; early life exposure; endophenotype; epidemiology study; gamma-Aminobutyric Acid; human disease; in vivo; insight; interdisciplinary approach; mouse model; neuronal excitability; neuroregulation; neurotoxicity; neurotoxicology; novel; patch clamp; pyrethroid; relating to nervous system; response; tandem mass spectrometry; therapeutic development; voltage

ABSTRACT Epidemiological studies identify early life exposure to pyrethroids as a threatening risk factor for attention- deficit hyperactivity disorder (ADHD). Because the reported risk of exposure is within no-observed-adverse- effect level (NOAEL) guidelines, environmental exposure to pyrethroids could be an underestimated leading cause of ADHD and other neurodevelopmental disorders in the general population. Animal models of early-life exposure to the pyrethroid pesticide deltamethrin (DM), a potent neurotoxin that acts on the insect voltage- gated Na+ (Nav) channel, recapitulates ADHD-like behavior through disruption of dopamine signaling in the nucleus accumbens (NAc), the brain region implicated in the human disease. Yet, the mechanism of toxicity of DM in the developing brain has not yet been determined. Recent studies from our group provide evidence for cross reactivity of DM with the mammalian Nav1.1 channel, an isoform expressed in fast-spiking parvalbumin (PV) inhibitory interneurons during development. These cells exert a powerful inhibitory control over the output of the NAc, which, if disrupted, leads to dopamine dysfunction with effects on locomotor activity, attention, and impulsivity, endophenotypes that characterize ADHD. In supporting studies conducted in an early-life DM exposure animal model we show regional accumulation of DM and loss in GABA in the NAc/striatum and demonstrate disruption of PV interneuron firing in the same brain region accompanied by ADHD-like behaviors. Building on this premise, we propose molecular (Aim 1), functional (Aim 2) and behavioral (Aim 3) studies to test the hypothesis that the primary mechanism of DM toxicity in the developing brain is to disrupt PV interneuron function leading to loss of local inhibitory control in the NAc and behavioral phenotypes common to ADHD. Outcomes of this study will provide new insights into the molecular-based understanding of risk factors for neurodevelopmental disorders providing guidance for therapeutic development against exposure.

抽象的 流行病学研究确定早期生命暴露于拟除虫菊酯作为关注的威胁风险因素 - 赤字多动症（ADHD）。因为报道的暴露风险在没有观察到的不良范围内 效应水平（NOAEL）指南，环境暴露于拟除虫菊酯可能是低估的领导 普通人群中多动症和其他神经发育障碍的原因。生命的动物模型 暴露于拟除虫菊酯农药三甲菊酯（DM），这是一种有效的神经毒素，作用于昆虫电压 - 封闭式Na+（NA+（NAV）通道，通过破坏多巴胺信号传导来概括类似ADHD的行为 伏隔核（NAC），大脑区域与人类疾病有关。然而，毒性的机制 发育中的大脑中的DM尚未确定。我们小组的最新研究提供了证据 DM与哺乳动物NAV1.1通道的交叉反应性，一种在快速刺激性白蛋白中表达的同工型 （PV）开发过程中抑制性神经元。这些单元对输出产生强大的抑制控制 NAC（如果受到破坏）会导致多巴胺功能障碍，对运动活动，注意力和 冲动性，表征多动症的内表型。在早期DM中进行的支持研究 暴露动物模型我们显示了NAC/纹状体中GABA中DM的区域积累和损失 证明在同一大脑区域中伴随着ADHD样行为的PV中间神经元发射的破坏。 在此前提的基础上，我们提出了分子（AIM 1），功能（AIM 2）和行为（目标3）研究 检验以下假设：发育中的大脑中DM毒性的主要机制是破坏PV 内神经元功能导致NAC和行为表型中局部抑制性控制的丧失，共有 多动症。这项研究的结果将为基于分子的风险因素的理解提供新的见解 对于神经发育障碍，为防止暴露的治疗发展提供了指导。