The USA sent approximately 700,000 troops to the Persian Gulf to participate in the 1990-91 Gulf War. Of those who returned, 25-30% complained of a generalized malaise with gastrointestinal, endocrinological, respiratory and neurological complaints, which was named Gulf War Illness (GWI). Many of those returning with GWI are still sick nearly 30 years after their exposure, with no cure. What changes allow these symptoms to persist over many years? Genetic variation among the troops may have caused them to respond differently to the exposure. Epigenetic alterations in gene regulation are the most likely candidate for the persistence of symptoms. We and others have developed an exposure regime in mice that mimics both troop exposures and biological effects of GWI. This model uses corticosterone pretreatment (CORT; to simulate physiological stress) combined with an irreversible acetylcholinesterase inhibitor, diisopropyl fluorophosphate (DFP); as troops were exposed to many acetylcholinesterase inhibitors. Initial studies showed acute changes in proinflammatory cytokine genes and changes in methylation of genes following exposure to CORT combined with DFP. PI Jones and colleagues have seen significant differences in proinflammatory gene expression response to the treatment among more than 25 different genotypes (i.e., inbred mouse strains) and have been able to map quantitative trait loci which mediate this effect. The proposed research takes the next step to understand the genetics of epigenetic changes related to the persistence of GWI.