Vester Aimée I, Chen Merry, Marsit Carmen J, Caudle W Michael
Department of Environmental Health Sciences, Emory University Rollins School of Public Health, Atlanta, GA 30329, USA.
Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USA.
Toxics. 2019 May 2;7(2):24. doi: 10.3390/toxics7020024.
Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood and previous studies indicate the dopamine system plays a major role in ADHD pathogenesis. Two environmental exposures independently associated with dopaminergic dysfunction and ADHD risk include exposure to deltamethrin, a pyrethroid insecticide, and chronic stress. We hypothesized that combined neurodevelopmental exposure to both deltamethrin and corticosterone (CORT), the major stress hormone in rodents, would result in additive changes within the dopamine system. To study this, we developed a novel dual exposure paradigm and exposed pregnant C57BL/6 dams to 3 mg/kg deltamethrin through gestation and weaning, and their offspring to 25 μg/mL CORT dissolved in the drinking water through adulthood. Midbrain RNA expression as well as striatal and cortical protein expression of key dopaminergic components were investigated, in addition to ADHD-like behavioral tasks and electrochemical dopamine dynamics via fast-scan cyclic voltammetry. Given the well-described sexual dimorphism of ADHD, males and females were assessed separately. Males exposed to deltamethrin had significantly decreased midbrain expression, decreased cortical tyrosine hydroxylase (TH) expression, increased activity in the Y maze, and increased dopamine uptake rate in the dorsal striatum. These effects did not occur in males exposed to CORT only, or in males exposed to both deltamethrin and CORT, suggesting that CORT may attenuate these effects. Additionally, deltamethrin- and CORT-exposed females did not display these dopaminergic features, which indicates these changes are sex-specific. Our results show dopaminergic changes from the RNA through the functional level. Moreover, these data illustrate the importance of testing multiple environmental exposures together to better understand how combined exposures that occur in certain vulnerable populations could affect similar neurodevelopmental systems, as well as the importance of studying sex differences of these alterations.
注意力缺陷多动障碍（ADHD）是儿童期最常见的神经发育障碍之一，先前的研究表明多巴胺系统在ADHD发病机制中起主要作用。两种与多巴胺能功能障碍和ADHD风险独立相关的环境暴露因素包括接触溴氰菊酯（一种拟除虫菊酯类杀虫剂）和慢性应激。我们假设，在神经发育过程中同时接触溴氰菊酯和皮质酮（CORT，啮齿动物体内主要的应激激素）会导致多巴胺系统产生累加性变化。为了研究这一点，我们开发了一种全新的双重暴露范式，在整个妊娠期和断奶期给怀孕的C57BL/6母鼠注射3mg/kg的溴氰菊酯，并在其后代成年后，让它们饮用溶解有25μg/mL CORT的饮用水。除了通过快速扫描循环伏安法进行类ADHD行为任务和电化学多巴胺动力学研究外，还对中脑RNA表达以及关键多巴胺能成分的纹状体和皮质蛋白表达进行了研究。鉴于ADHD存在明显的性别差异，我们分别对雄性和雌性进行了评估。接触溴氰菊酯的雄性中脑表达显著降低，皮质酪氨酸羟化酶（TH）表达减少，在Y迷宫中的活动增加，背侧纹状体中的多巴胺摄取率升高。这些效应在仅接触CORT的雄性或同时接触溴氰菊酯和CORT的雄性中并未出现，这表明CORT可能会减弱这些效应。此外，接触溴氰菊酯和CORT的雌性并未表现出这些多巴胺能特征，这表明这些变化具有性别特异性。我们的研究结果显示了从RNA水平到功能水平的多巴胺能变化。此外，这些数据说明了共同测试多种环境暴露因素对于更好地理解特定脆弱人群中发生的联合暴露如何影响相似的神经发育系统的重要性，以及研究这些改变的性别差异的重要性。
