PDF(Pubmed)
Abstract：
Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit-to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.
摘要：
海湾战争疾病（GWI）是大约25万海湾战争（GW）退伍军人的主要健康问题。但GWI的病因尚不清楚。我们假设线粒体功能障碍是GWI的重要原因，基于某些GWI症状与某些线粒体疾病中发生的症状的相似性;GW退伍军人暴露的某些污染物影响线粒体的合理性;GWI实验室模型研究中观察到的线粒体效应;以及GW退伍军人研究中线粒体结局的先前证据。线粒体的主要作用是通过氧化磷酸化产生能量。然而,直接评估线粒体呼吸，反映氧化磷酸化，在GWI的退伍军人中没有进行过。在这项病例对照观察研究中，我们在一组114GW的退伍军人中测试了线粒体功能和完整性的多种测量方法，根据堪萨斯州的定义，有80和没有GWI的34。在循环的白细胞中，我们分析了线粒体呼吸和细胞外酸化的多种测量方法，非需氧能量产生的代表;线粒体DNA(mtDNA)拷贝数;mtDNA损伤;和核DNA损伤。我们还收集了有关人口统计的详细调查数据；部署；自我报告的农药暴露，溴化吡啶斯的明,以及化学和生物战剂；以及当前的生物识别技术，健康和活动水平。我们观察到GWI退伍军人血液中mtDNA含量增加了9%，但没有检测到DNA损伤的差异。没有GWI的退伍军人的基础和与ATP相关的耗氧量分别高出42％和47％，在调整mtDNA量后。我们没有发现无氧能量产生补偿性增加的证据：GWI中的细胞外酸化也较低（基线时低12％）。27名和26名退伍军人返回第二次和第三次访问，允许我们测量线粒体参数随时间的稳定性。mtDNACN,mtDNA损伤，ATP连接的OCR，备用呼吸容量随着时间的推移是中等可复制的，组内相关系数分别为0.43、0.44、0.50和0.57。其他指标显示出较高的就诊变异性。与没有GWI的退伍军人相比，许多测量结果显示，随着时间的推移，GWI退伍军人的可复制性较低。最后,我们发现召回的农药接触之间有很强的关联，溴化吡啶斯的明,以及化学和生物战剂和GWI（分别为p<0.01，p<0.01和p<0.0001）。我们的结果表明线粒体呼吸功能下降，糖酵解活性下降，这两者都与能源可用性下降是一致的，在GWI退伍军人的外周血单核细胞中。
