Corticosterone primes the neuroinflammatory responses to Gulf War Illness associated exposures: effects of irreversible vs. reversible acetylcholinesterase inhibitors

Details

• Personal Author:
  Kelly KA ; Locker AR ; Michalovicz LT ; Miller DB ; O'Callaghan JP
• Description:
  Following the 1991 Persian Gulf War, as many as 250,000 soldiers returned with symptoms of Gulf War Illness (GWI), a complex disorder with characteristics similar to neuroinflammation-driven "sickness behavior." These troops were exposed to a variety of cholinesterase inhibitors during deployment, including exposures to irreversible organophosphate (OP) acetylcholinesterase inhibitors (AChEI), in the form of the insecticide [chlorpyrifos (CPO)], or to warfare nerve agent, sarin. The reversible AChEI, pyridostigmine bromide (PB), was self-administered by soldiers as prophylactic treatment for potential nerve agent exposures. Alongside exposure to these AChEIs in the Gulf War were physiological stressors (e.g., high temperatures, physical exercise, or physical threat). Here, we examined effects of exposure to 3 OPs: CPO, DFP (as sarin surrogate), and PB in mice. These AChEIs were given alone and with pretreatment with the stress hormone corticosterone (CORT) to mimic high levels of physiological stress. We assessed effects of these treatments on brain regional neuroinflammation by qPCR and neuroinflammation-associated microglial/astroglial activation by levels of phosphorylation of STAT3(tyr705). Adult male C57BL/6J mice were exposed to CORT (400mg/L in 1.2% EtOH), or water for 4 days. On the 5th day, mice were exposed to a single i.p. dose of CPO (8.0mg/kg), DFP (4.0mg/kg), or PB (3.0mg/kg). qPCR at 6 hours postexposure revealed that acute CPO and DFP treatment alone produced neuroinflammation in the cortex and hippocampus that was enhanced by CORT pretreatment. Furthermore, CORT + CPO or DFP exposure enhanced activation of STAT3 in both brain regions. In contrast, acute exposure to PB alone or with CORT pretreatment did not produce significant increases in neuroinflammation or STAT3 activation. Exposure to the irreversible (CPO, DFP) or reversible (PB) AChEI with or without CORT pretreatment did not result in astrogliosis (increases in GFAP) in either the cortex or hippocampus, findings suggestive of an initial lack of neurodegeneration. Overall, exposure to irreversible AChEIs, CPO and DFP, produce neuroinflammatory effects in the cortex and hippocampus that are augmented by CORT pretreatment, an effect not seen with exposure to the reversible AChEI, PB. These effects may be a result of selective CORT priming of the JAK2/STAT3 pathway for specific GWI-related compounds - an effect that does not induce early signs of neurodegeneration. Thus, this study reveals the potential for selective pathway activation by irreversible AChEIs, a stress-hormone primed neuroinflammation in the absence of neurodegeneration that results in symptoms of GWI. [Description provided by NIOSH]
• Subjects:
  Animals Behavior Chemical Warfare Agents Chemistry Hypersensitivity Insecticides Laboratories Nervous System Nervous System Diseases Occupational Health Risk Assessment Risk Factors Safety

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• Keywords:
  Chemical-composition Chemical-hypersensitivity Chemical-properties Chemical-reactions Chemical-warfare-agents Exposure-levels Insecticide-poisoning Laboratory-animals Military-personnel Neurological-diseases Neurological-reactions Neurological-system Physiological-disorders Physiological-effects Physiological-response Physiology Risk-factors Stress

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• Publisher:
  Society for Neuroscience
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• NIOSHTIC Number:
  nn:20047011
• Citation:
  Neuroscience 2015, October 17-21, 2015, Chicago, Illinois. Washington, DC: Society for Neuroscience, 2015 Oct; :523.01/V36
• CAS Registry Number:
  Pyridostigmine bromide (CAS RN 101-26-8)
• Federal Fiscal Year:
  2016
• Peer Reviewed:
  False
• Source Full Name:
  Neuroscience 2015, October 17-21, 2015, Chicago, Illinois
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:0805ebc61095b608ee87593140ef271f045c21a4b2e8fdbac782dae8490504cd71b13b9be15b29edfaa63386c1a68a160b994db6999e2c0a42c7dab97a9cd87f
• Download URL:
  https://stacks.cdc.gov/view/cdc/202248/cdc_202248_DS1.pdf
• File Type:
  [PDF - 68.14 KB ]