We have shown previously that chronic exposure to the glucocorticoid corticosterone, (CORT), at levels associated with high physiological stress, can prime the CNS proinflammatory response to neurotoxic insults. Persistent sickness behavior, a prominent component of Gulf War (GW) Illness, is associated with neuroinflammation. Veterans of the 1991 GW were exposed to the stresses of war, prophylactic treatment with the reversible acetylcholinesterase (AChE) inhibitor, pyridostigmine bromide (PB), the insect repellent, DEET, and, potentially, acutely to the nerve agent sarin. Previously, we showed that subchronic CORT pretreatment primed the CNS to mount a neuroinflammatory response to these GW exposures when provoked 24 h after the termination of CORT treatment. Here, we investigated the persistence of this priming effect on neuroinflammation and the minimal amount of CORT required to produce the priming response. Male C57BL/6 mice were pretreated with chronic (14 days) PB (2mg/kg/day, s.c.) and DEET (30 mg/kg/day, s.c.), as well as subchronic CORT (200 microg/ml in drinking water on days 7-14) or acute CORT (20 mg/kg, s.c., 2 injections, 7 h interval on day 14) exposures. Acute doses (days 15 or 45) of the sarin surrogate and irreversible AChE inhibitor diisopropyl phophorofluoridate (DFP, 4 mg/kg, i.p.) or known inflammogen lipopolysaccharide (LPS, 2 mg/kg, s.c.) were used to provoke neuroinflammation. We found that both acute and chronic CORT exposure greatly augmented neuroinflammation in response to LPS and DFP. Marked neuroinflammation in response to DFP was found even when the exposure was 30 days after the cessation of the subchronic CORT treatment (a time point equivalent to 6 years in humans). Our findings are suggestive of a possible critical and yet unrecognized link between the stressful environs of the 1991 GW theater and agent exposure(s) unique to this war, exposures in which the CNS is primed to amplify future exposure to pathogens, injury or toxicity.
Toxicology; Corticoids; Corticosteroids; Military-personnel; Mental-stress; Soldiers; Immune-reaction; Neurotoxic-effects; Physiological-response; Physiological-stress; Acetylcholinesterase; Insect-repellents; Bromides; Laboratory-animals; Exposure-assessment; Exposure-levels; Dose-response; Chronic-exposure; Central-nervous-system
The Toxicologist. Society of Toxicology 52nd Annual Meeting and ToxExpo, San Antonio, Texas, March 10-14, 2013