Department of Biological Sciences and Center for Environmental Epigenetics and Development and Department of Cell and Systems Biology, University of Toronto, Scarborough campus, Toronto, ON, Canada.
Present address: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, 38103, USA.
J Neuroinflammation. 2018 Mar 17;15(1):86. doi: 10.1186/s12974-018-1113-9.
Gulf War illness (GWI) is an archetypal, medically unexplained, chronic condition characterised by persistent sickness behaviour and neuroimmune and neuroinflammatory components. An estimated 25-32% of the over 900,000 veterans of the 1991 Gulf War fulfil the requirements of a GWI diagnosis. It has been hypothesised that the high physical and psychological stress of combat may have increased vulnerability to irreversible acetylcholinesterase (AChE) inhibitors leading to a priming of the neuroimmune system. A number of studies have linked high levels of psychophysiological stress and toxicant exposures to epigenetic modifications that regulate gene expression. Recent research in a mouse model of GWI has shown that pre-exposure with the stress hormone corticosterone (CORT) causes an increase in expression of specific chemokines and cytokines in response to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor.
C57BL/6J mice were exposed to CORT for 4 days, and exposed to DFP on day 5, before sacrifice 6 h later. The transcriptome was examined using RNA-seq, and the epigenome was examined using reduced representation bisulfite sequencing and H3K27ac ChIP-seq.
We show transcriptional, histone modification (H3K27ac) and DNA methylation changes in genes related to the immune and neuronal system, potentially relevant to neuroinflammatory and cognitive symptoms of GWI. Further evidence suggests altered proportions of myelinating oligodendrocytes in the frontal cortex, perhaps connected to white matter deficits seen in GWI sufferers.
Our findings may reflect the early changes which occurred in GWI veterans, and we observe alterations in several pathways altered in GWI sufferers. These close links to changes seen in veterans with GWI indicates that this model reflects the environmental exposures related to GWI and may provide a model for biomarker development and testing future treatments.
海湾战争病（GWI）是一种典型的、医学上无法解释的慢性疾病，其特征是持续的疾病行为以及神经免疫和神经炎症成分。据估计，在 1991 年海湾战争的 90 多万名退伍军人中，有 25%-32%符合 GWI 诊断要求。有人假设，战斗中的高身心压力可能会增加对不可逆乙酰胆碱酯酶（AChE）抑制剂的易感性，从而导致神经免疫系统的启动。许多研究将高水平的身心压力和有毒物质暴露与调节基因表达的表观遗传修饰联系起来。最近在 GWI 的小鼠模型中的研究表明，预先暴露于应激激素皮质酮（CORT）会导致在接触沙林替代品和不可逆 AChE 抑制剂二异丙基氟磷酸酯（DFP）时，特定趋化因子和细胞因子的表达增加。
C57BL/6J 小鼠接受 CORT 处理 4 天，然后在第 5 天接受 DFP 处理，6 小时后处死。使用 RNA-seq 检查转录组，使用简化代表性亚硫酸氢盐测序和 H3K27ac ChIP-seq 检查表观基因组。
我们显示了与免疫和神经元系统相关的基因的转录、组蛋白修饰（H3K27ac）和 DNA 甲基化变化，这些变化可能与 GWI 的神经炎症和认知症状有关。进一步的证据表明，在 GWI 患者中，额叶皮层中的髓鞘形成少突胶质细胞的比例发生改变，这可能与 GWI 患者的白质缺陷有关。
我们的发现可能反映了 GWI 退伍军人中早期发生的变化，我们观察到 GWI 患者中几个发生改变的途径。这些与 GWI 退伍军人变化的密切联系表明，该模型反映了与 GWI 相关的环境暴露，并且可能为生物标志物的开发和测试未来的治疗方法提供模型。
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