Volatile organic compound effects on brain and behavior

挥发性有机化合物对大脑和行为的影响

• 批准号: 10118080
• 负责人: Kevin D. Beck
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10118080
• 关键词: 3-nitrotyrosine; Address; Affect; Aging; Animal Model; Area; Autopsy; Behavior; Behavior assessment; Behavioral; Biological; Brain; Chronic; Corpus striatum structure; Detection; Development; Dopamine; Dorsal; Dose; Exhibits; Experimental Designs; Exposure to; Face; Family; Goals; Gulf War; Harvest; Health; Health Care Costs; High Pressure Liquid Chromatography; Individual; Ingestion; Knowledge; Longitudinal Studies; Measures; Medical; Medical center; Methods; Microglia; Modeling; Molecular Analysis; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Nitrates; Ohio; Olive oil preparation; Oranges; Parkinson Disease; Pathology; Pilot Projects; Poison; Poisoning; Pollution; Proteins; Public Health; Publishing; Rattus; Recording of previous events; Research; Research Design; Research Personnel; Rodent; Signal Transduction; Source; Stains; Stress; Substantia nigra structure; Testing; Tetrachloroethylene; Time; Tissues; Toxic effect; Toxicology; Trichloroethylene; Tyrosine 3-Monooxygenase; Universities; Veterans; Water; Water Supply; Work; base; behavior test; brain behavior; brain tissue; contaminated drinking water; contaminated water; disease registry; dopaminergic neuron; dosage; drinking water; exposed human population; ground water; health assessment; motor impairment; neurobehavioral; neuroinflammation; neuropathology; neurotoxic; neurotoxicity; nigrostriatal pathway; pars compacta; programs; response; volatile organic compound

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.

抽象的 驻扎在北卡罗来纳州勒琼军营的多达一百万人可能已中毒 暴露于渗入基础饮用水的挥发性有机化合物 (VOC) 1953 年至 1987 年。退伍军人管理局现在承担 Lejeune 营退伍军人和平民的医疗费用 期间驻扎在基地的工作人员和居民家庭进行了各种健康检查 包括帕金森病 (PD) 在内的两种主要污染物。 三氯乙烯（TCE）和四氯乙烯（PCE）的毒性作用尚未显示 导致 PD 的水平在饮酒中记录的水平的 100 倍以内 当给啮齿类动物亚慢性喂食时，三氯乙烯（TCE）和四氯乙烯（PCE）含量非常高时会导致帕金森病（PD）。 仅当与 TCE 联合使用时，才建议在动物模型中引发 PD。 过去研究中使用的 TCE 或 PCE 的持续时间和剂量均与训练营近似 因此，该试点项目的目标是记录 Lejeune 平均暴露量估计值。 慢性 TCE（有或没有 PCE）暴露所必需的基本参数 长期在水中给药时 PD 神经毒性的行为和生物学症状 我们的工作假设是通过饮用水长期摄入三氯乙烯和四氯乙烯。 导致行为改变，是黑质潜在神经炎症的指标 大脑的致密部（SNPC），随着持续摄入，最终会导致 SNPC 多巴胺 (DA) 神经元的神经变性（即 PD 的发展）。 通过评估暴露大鼠的功能和神经病理学，可以验证这一假设 2 目标 目标 1 将重点确定饮用水 TCE​​ 对 PD 的可能贡献。 已确定的亚慢性毒性每日灌胃 TCE 剂量将延长超过 6 个。 饮用水中的一个月时间，以确定总累积暴露量是否可以预测 诱导 PD 或 TCE 是否需要每日高浓度来诱导 PD。 类似的实验设计，目标 2 将确定是否将 PCE 添加到受 TCE 污染的 饮用水通过行为测试增强功能评估的诱导， 将在 TCE 或 TCE+PCE 暴露期间和之后发生 在每个时间点，大鼠将发生。 完成最后一项后评估运动协调性和感觉运动反应性。 暴露行为测试，所有大鼠将被采集大脑用于后续大脑 将评估大脑纹状体和 DA 代谢物的水平。 这些尸检分析与 SNPC 的神经炎症/神经病理学相结合。 随着时间的推移，重复的行为测试将提供第一个证据：是否长期饮水 TCE 或 TCE+PCE 污染足以导致类似 PD 的运动障碍或 彻底的PD。