Genetic and epigenetic analysis implicates central myelin as a major target of Gulf War illness

In 1991, the USA sent 700,000 troops to the first Gulf War. Between 25 and 35 percent became ill with a multi-symptom malady now known as Gulf War Illness (GWI). Among the symptoms are neurological signs ranging from cognitive difficulties, chronic pain, lethargy and chronic fatigue. The cause of these symptoms is believed to be exposure to organophosphates, including sarin and insecticides coupled with high circulating glucocorticoids as might be expected in combat. This exposure increases the expression of proinflammatory cytokines, which in turn inhibits the production of myelin, a major pathophysiological sign of GWI. Recently, we conducted a study in a genetic reference population of mice to show acute and chronic effects of the model exposure to diisopropylfluorophosphate, a sarin surrogate combined with corticosterone. We also sought to understand the genetic basis for the differences between those who became sick, all else being equal, and those who did not. In the acute work, we showed the combination to increase expression of proinflammatory cytokine genes and decrease expression of several genes that regulate myelin. We also sought to understand the chronic nature of the disease, so we conducted a study of the epigenetic manifestations of our model exposome. The results of this study revealed extensive methylation of Eif2B5 a gene that has major influence on the production of myelin. This result is consistent with the results of the acute study, i.e., the model GWI exposome has major effects on myelin. These findings indicate myelin as target for GWI therapeutics.