Neurotoxicology of deltamethrin in the developing brain

摘要 流行病学研究确定生命早期暴露于拟除虫菊酯是一个值得关注的威胁性风险因素- 缺陷多动障碍（ADHD）。由于报告的暴露风险在未观察到的不良反应范围内， 根据无明显不良作用水平（NOAEL）指南，拟除虫菊酯的环境暴露可能被低估， ADHD和其他神经发育障碍的原因。早期生命的动物模型 接触拟除虫菊酯类杀虫剂溴氰菊酯（DM），一种作用于昆虫电压的强效神经毒素- 门控Na+（Nav）通道，通过破坏多巴胺信号传导来重现ADHD样行为。 脑桥核（NAc），与人类疾病有关的大脑区域。然而，毒性的机制， 发育中的大脑中的DM尚未确定。我们小组最近的研究提供了证据， DM与哺乳动物Nav1.1通道的交叉反应性，Nav1.1通道是一种在快速加标小清蛋白中表达的同种型 (PV)在发育过程中抑制中间神经元。这些细胞对输出施加强有力的抑制控制 如果NAc被破坏，会导致多巴胺功能障碍，影响运动活动，注意力， 冲动性和多动症的内在表现型支持在早期糖尿病患者中进行的研究 暴露动物模型中，我们显示NAc/纹状体中DM的区域积累和GABA的损失， 证明PV中间神经元放电在相同的脑区域伴随ADHD样行为的中断。 在此前提下，我们提出了分子（目标1），功能（目标2）和行为（目标3）研究， 检验DM毒性在发育中大脑中的主要机制是破坏PV的假设 中间神经元功能导致NAc中局部抑制控制的丧失， 多动症。这项研究的结果将为基于分子的风险因素理解提供新的见解 为神经发育障碍提供了针对暴露的治疗开发指导。

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.