Epigenetic study of the long-term effects of Gulf War illness

Byron C Jones^1*James P O'Callaghan²David G Ashbrook¹Lu Lu¹Pjotr Prins¹WENYUAN ZHAO¹Khyobeni Mozhui^3*

• ¹Genetics, Genomics and Informatics, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States
• ²Division of Health Effects Laboratory, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention (CDC), Morgantown, West Virginia, United States
• ³Preventive Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States

Gulf War Illness is a chronic multisymptomatic disorder that affects as many as 25-35% of the military personnel who were sent to the Persian Gulf war in 1991. The illness has many debilitating symptoms, including cognitive problems, gastrointestinal symptoms, and musculoskeletal pain. Those so afflicted have been sick for more than 30 years and, therefore, it has become imperative to understand the etiology of Gulf War Illness and then produce treatments to ease the symptoms. We hypothesized that the length of the disease was reflected in epigenetic modification of possibly several genes related to the symptoms. We subjected male and female mice from 11 BXD strains to combined corticosterone and the sarin surrogate, diisopropylfluorophosphate, to emulate the physiological stress of war and the potential exposures to organophosphate pesticides and nerve agent in theater. Three hundred days after treatment, we used Methyl-CpG-binding domain sequencing (MBD-seq) to assay genome-wide methylation. The analysis revealed 20 methylated genes, notably Eif2b5, that regulates myelin production. Loss of myelin with accompanying musculoskeletal pain is a major symptom of Gulf War Illness. Our work demonstrates multiple genes were methylated by exposure to organophosphates and glucocorticoids. These genes point to biochemical mechanisms that may be targets for therapeutic interventionWeek 1, days 1-7, Corticosterone in the drinking water Week 2, day 1 (eight days since corticosterone treatment) i.p. injection of 4 mg/kg DFP Week 3, days 2-7 no corticosterone in the drinking water Weeks 4-12 Corticosterone in drinking water on alternate weeks beginning with week 4 Weeks 13-41 No treatments Week 42 Corticosterone in drinking water Week 43 day 1, euthanize mice, harvest tissue Mouse n=5 per strain, sex, and treatment.