Translational potential of long-term decreases in mitochondrial lipids in a mouse model of Gulf War Illness
Translational potential of long-term decreases in mitochondrial lipids in a mouse model of Gulf War Illness
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DOI：
10.1016/j.tox.2016.10.012
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发表时间：
2016-11-30
期刊：
影响因子：
4.5
通讯作者：
Crawford, Fiona
中科院分区：
文献类型：
--
作者：
Abdullah, Laila;Evans, James E.;Crawford, Fiona
海湾战争病（GWI）影响了1990-1991年海湾战争（GW）中25%的退伍军人，并伴有与记忆处理有关的大脑区域的损伤。二十五年后，GWI的慢性病理学仍然无法解释。为了解决这个问题，我们研究了GW暴露在一个既定的GWI小鼠模型的长期后果，以确定相关的GWI的慢性症状的生物过程。将三个月大的雄性C57 BL 6小鼠暴露于GW药剂（溴化吡啶斯的明和氯菊酯）10天。在暴露后15个月和16个月进行的巴恩斯迷宫测试显示学习和记忆障碍。免疫组织化学分析显示，星形胶质细胞和小胶质细胞的激活，在接触小鼠的大脑皮层。蛋白质组学研究确定了线粒体功能的扰动，代谢组学数据显示，暴露小鼠大脑中的克雷布斯循环化合物、乳酸盐、β-羟基丁酸盐和甘油-3-磷酸盐减少。脂质组学数据显示，暴露小鼠大脑中的脂肪酸、酰基肉毒碱和磷脂（包括心磷脂）减少。初步生物标志物研究表明，与各自的对照组相比，暴露于GWI的小鼠和退伍军人的血浆中奇链增加，长链酰基肉毒碱减少。与对照组相比，GWI退伍军人的极长链酰基肉毒碱减少。这些研究表明，线粒体（脂质紊乱）可能与GWI有关，需要进一步研究以确定其在这种疾病的病理生理学中的作用。针对线粒体功能可能为GWI提供有效的治疗方法，脂质异常可作为GWI的生物标志物。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Gulf War Illness (GWI) affects 25% of veterans from the 1990-1991 Gulf War (GW) and is accompanied by damage to the brain regions involved in memory processing. After twenty-five years, the chronic pathobiology of GWI is still unexplained. To address this problem, we examined the long-term consequences of GW exposures in an established GWI mouse model to identify biological processes that are relevant to the chronic symptoms of GWI. Three-month old male C57BL6 mice were exposed for 10 days to GW agents (pyridostigmine bromide and permethrin). Barnes Maze testing conducted at 15- and 16-months post-exposure revealed learning and memory impairment. Immunohistochemical analyses showed astroglia and microglia activation in the hippocampi of exposed mice. Proteomic studies identified perturbation of mitochondria function and metabolomics data showed decreases in the Krebs cycle compounds, lactate, beta-hydroxybutyrate and glycerol-3 phosphate in the brains of exposed mice. Lipidomics data showed decreases in fatty acids, acylcarnitines and phospholipids, including cardiolipins in the brains of exposed mice. Pilot biomarker studies showed that plasma from exposed mice and veterans with GWI had increases in odd-chain, and decreases in long-chain, acylcarnitines compared to their respective controls. Very long-chain acylcarnitines were decreased in veterans with GWI compared to controls. These studies suggest that mitochondria( lipid disturbances might be associated with GWI and that further investigation is required to determine its role in the pathophysiology of this illness. Targeting mitochondrial function may provide effective therapies for GWI, and that lipid abnormalities could serve as biomarkers of GWI. (C) 2016 Elsevier Ireland Ltd. All rights reserved.