Volatile organic compound effects on brain and behavior

摘要 多达一百万人驻扎在北卡罗来纳州的勒琼营， 暴露于挥发性有机化合物（VOC），这些化合物已渗入基础饮用水 从1953年到1987年退伍军人事务部现在正在支付勒琼营退伍军人、平民 工作人员和居民家庭驻扎在基地在这段时间的各种健康 包括帕金森病（PD）。尽管如此，两个主要的污染物牵连在 三氯乙烯（TCE）和四氯乙烯（PCE）的毒性效应尚未显示 导致PD的水平在100倍内的记录已经存在的饮用水 水当对啮齿动物亚慢性给药时，TCE可导致非常高水平的PD，而PCE 只有在动物模型中，当它与TCE组合时，才被建议引发PD。 在过去的研究中使用的TCE或PCE的持续时间和剂量都不接近Camp。 Lejeune平均暴露估计值。因此，该试点项目的目标是记录 慢性TCE（含和不含PCE）暴露的基本参数 在水中长期给药时PD神经毒性的行为和生物学体征 供应我们的工作假设是，通过饮用水长期摄入TCE + PCE 导致黑质潜在神经炎症的行为变化 大脑的腹侧部（SNPC），随着持续摄入，最终导致 SNPC多巴胺（DA）神经元的神经变性（即PD的发展）。测试 通过评估暴露大鼠的功能和神经病理学， 2个目标。目标1将侧重于确定饮用水三氯乙烯对PD的可能贡献 病理已确定的毒性亚慢性每日灌胃TCE剂量将延长至6 一个月的时间内在饮用水中，以确定是否总累积暴露预测 诱导PD，或者如果TCE诱导PD需要每日高浓度。后 类似的实验设计，目标2将确定向三氯乙烯污染的 饮用水增强PD的诱导。通过行为测试进行功能评估， 将在TCE或TCE + PCE暴露期间和之后发生。在每个时间点，大鼠将 评估运动协调和感觉运动反应。在完成最后一个职位后- 暴露行为测试，所有大鼠将收获其大脑用于随后的大脑 评估。将评估大脑纹状体中的DA和DA代谢物水平， SNPC中的神经炎症/神经病理学。这些尸检分析， 随着时间的推移，反复的行为测试将提供第一个证据，如果长期饮用水， TCE或TCE + PCE的污染足以导致PD样运动障碍，或 完全的警察局

Abstract Up to one million individuals stationed at Camp Lejeune, NC may have been poisoned by exposure to volatile organic compounds (VOCs) that had leached into the base drinking water from 1953 – 1987. The VA is now covering the health costs for Camp Lejeune veterans, civilian staff, and the resident families stationed at the base during that time for a variety of health conditions, including Parkinson's Disease (PD). Still, two of the main contaminants implicated in the toxic effects, trichloroethylene (TCE) and tetrachloroethylene (PCE), have yet to be shown to cause PD at the levels within 100-fold of those documented to have existed in the drinking water. TCE can cause PD at very high levels when given sub-chronically to rodents, and PCE has only been suggested to elicit PD in the animal models when it is combined with TCE. Neither the duration nor the dose of TCE or PCE used in past studies approximated the Camp Lejeune average exposure estimates. Therefore, the goal of this pilot project is to document the basic parameters necessary for chronic TCE (with and without PCE) exposure to cause behavioral and biological signs of PD neurotoxicity when delivered chronically in the water supply. Our working hypothesis is that chronic TCE+PCE ingestion through drinking water leads to behavioral changes indicative of underlying neuroinflammation in the substantia nigra pars compacta (SNPC) of the brain that, with continued ingestion, eventually leads to neurodegeneration of the SNPC dopamine (DA) neurons (i.e. development of PD). The testing of this hypothesis will occur by assessing function and neuropathology in exposed rats through 2 aims. Aim 1 will focus upon determining the possible contribution of drinking water TCE to PD pathology. An established toxic sub-chronic daily gavage TCE dose will be extended over a 6 month period in the drinking water to determine if the total cumulative exposure predicts the induction of PD or if daily high concentrations are necessary for TCE to induce PD. Following a similar experimental design, Aim 2 will determine if the addition of PCE to TCE-contaminated drinking water potentiates the induction of PD. Functional assessments, via behavioral testing, will occur during and following TCE or TCE+PCE exposure. At each time-point, rats will be assessed for motor coordination and sensorimotor reactivity. Upon completion of the last post- exposure behavioral test, all rats will have their brains harvested for subsequent brain assessments. The brains will be assessed for DA and DA-metabolite levels in the striatum and neuroinflammation/neuropathology in the SNPC. These post-mortem analyses, combined with the repeated behavioral testing over time, will provide the first evidence if chronic drinking water contamination by TCE or TCE+PCE are sufficient to cause a PD-like motor impairments or outright PD.