Corticosterone and pyridostigmine/DEET exposure attenuate peripheral cytokine expression: Supporting a dominant role for neuroinflammation in a mouse model of Gulf War Illness

• Published in: Neurotoxicology (Park Forest South) 2019-01, Vol.70, p.26-32
• Main Authors: Michalovicz, Lindsay T., Locker, Alicia R., Kelly, Kimberly A., Miller, Julie V., Barnes, Zachary, Fletcher, Mary Ann, Miller, Diane B., Klimas, Nancy G., Morris, Mariana, Lasley, Stephen M., O’Callaghan, James P.
• Format: Article
• Language: English
• Subjects: Animals; Brain; Chlorpyrifos; Cholinesterase Inhibitors - administration & dosage; Cholinesterase Inhibitors - toxicity; Constellations; Corticosterone; Corticosterone - administration & dosage; Corticosterone - toxicity; Cytokines; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Cytokines - genetics; DEET; DEET - administration & dosage; DEET - toxicity; Diisopropyl fluorophosphate; Disease Models, Animal; Etiology; Exposure; Gene Expression; Gulf War; Gulf war illness; Gulf War syndrome; Inflammation; Inflammation - blood; Inflammation - chemically induced; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - blood; Insect Repellents - administration & dosage; Insect Repellents - toxicity; Liver; Male; Mice; Mice, Inbred C57BL; Military personnel; Mimicry; Organic chemistry; Organophosphates; Persian Gulf Syndrome - blood; Persian Gulf Syndrome - chemically induced; Persian Gulf War; Pesticides; Physiological effects; Pyridostigmine; Pyridostigmine bromide; Pyridostigmine Bromide - administration & dosage; Pyridostigmine Bromide - toxicity; Sarin; Sickness behavior; Signs and symptoms; Stress (physiology); War
• ISSN: 0161-813X; 1872-9711; 1872-9711
• DOI: 10.1016/j.neuro.2018.10.006

•Sarin surrogate, DFP, causes minimal increases in cytokines in liver and blood.•Unlike results for the brain, CORT does not prime peripheral cytokine responses.•PB/DEET generally suppresses cytokine levels in our model of Gulf War Illness.•Lack of CORT priming in periphery supports a neuroimmune basis of Gulf War Illness. Gulf War Illness (GWI) is a chronic multi-symptom disorder experienced by as many as a third of the veterans of the 1991 Gulf War; the constellation of “sickness behavior” symptoms observed in ill veterans is suggestive of a neuroimmune involvement. Various chemical exposures and conditions in theater have been implicated in the etiology of the illness. Previously, we found that GW-related organophosphates (OPs), such as the sarin surrogate, DFP, and chlorpyrifos, cause neuroinflammation. The combination of these exposures with exogenous corticosterone (CORT), mimicking high physiological stress, exacerbates the observed neuroinflammation. The potential relationship between the effects of OPs and CORT on the brain versus inflammation in the periphery has not been explored. Here, using our established GWI mouse model, we investigated the effects of CORT and DFP exposure, with or without a chronic application of pyridostigmine bromide (PB) and N,N-diethyl-meta-toluamide (DEET), on cytokines in the liver and serum. While CORT primed DFP-induced neuroinflammation, this effect was largely absent in the periphery. Moreover, the changes found in the peripheral tissues do not correlate with the previously reported neuroinflammation. These results not only support GWI as a neuroimmune disorder, but also highlight the separation between central and peripheral effects of these exposures.