Modeling the behavioral and metabolic phenotype of mice exposed to Gulf War toxicants

Abstract

Gulf War Illness (GWI) is a chronic multi‐symptom condition that still affects a third of veterans who served in the 1991 Persian Gulf War (GW). Latently‐emerging and persistent symptoms fall into 5 general domains: neurological/cognition/mood (memory, concentration, anxiety, depression), muscle/joint pain, respiratory, gastrointestinal disturbances and especially chronic fatigue. GWI remains untreated due its poorly understood etiology and pathophysiology. It is suggested that GWI is a result of continuous exposure to GW agents administered to protect military personnel: 1) acetylcholinesterase inhibitor pyridostigmine bromide (PB) taken orally as prophylaxis against nerve agents, 2) topical insecticide permethrin (PER), and 3) topical insect repellent diethyltoluamide (DEET). Although GW agents were administered at safe doses, their chronic and combined use, in addition to stress, a critical component of GW deployment, may produce and/or intensify the pathophysiology of GWI for reasons not fully understood. Additionally, GW veterans report symptoms associated with delayed‐onset Type II diabetes mellitus, which may be associated with chronic fatigue. To further investigate the behavioral, metabolic manifestations of GWI pathophysiology, we studied the effects of acute (AE) and chronic (CE) GW toxicant exposure in adult C57Bl/6N males utilizing a repeated measures design. The AE model consisted of 1wk exposure to PB (2 mg/kg/d; ip), PER (200 mg/kg/d in 70% ETOH; top), DEET (40 mg/kg/d in ETOH; top) and 5 min restraint stress/d (n=4–7). The CE model consisted of 5 days/week for 28 days of exposure to PB (13 mg/kg/d; po), PER (1.3 mg/kg/d; top) in 70% ETOH, DEET (40 mg/kg/d in ETOH; top) and stress 5min/d (n=6–8). A sham control was also tested in CE experiments. Behavioral and metabolic endpoints were measured at one week post treatment (PT) and 60d PT (AE) and 90d PT (CE) to model the delayed and persistent effects seen in GW veterans. When compared to pre‐treatment, GW mice exposed to CE paradigm showed depressive‐like behavior on forced swim, tail suspension and hanging wire tests at post‐treatment. On elevated platform (SUOK) test AE and CE produced sensorimotor alterations as measured by an increased number segments crossed CE decreased missteps/segments crossed relative to pre‐treatment. Increased anxiety was observed as decreased risk assessment (CE) and increased vegetative behavior in AE on SUOK and in AE and CE as less percent time spent in open arm of an elevated plus maze. GW agent exposure had no effect on three‐chambered sociability test. Both CE and AE groups displayed transient but marked insulin insensitivity relative to pre‐treatment. These results show that GW agents can produce insulin insensitivity along with altered sensorimotor integration, anxiety and depressive‐like behavior. In comparison to GW effects on anxiety which persisted at 90d PT (with the exception of vegetative behavior), the depressive‐like effects normalized at 90d PT. Our findings will help inform studies that aim to elucidate the etiology and pathophysiology of GWI.Support or Funding InformationAmerican Physiological Society (AB) and UC Minigrant (AB and JT).