A Network Approach to Phosphoprotein Signaling in a Mouse Model of Gulf War Illness Using Corticosterone and Diisopropyl Fluorophosphate

Details

• Personal Author:
  Boyd J ; Kelly K ; Michalovicz L ; Miller J ; O'Callaghan J ; Penatzer JA ; Prince N
• Description:
  An estimated 3 million people are exposed to organophosphates each year; however, many do not report acute effects, but report symptoms of adverse neurological effects years later, as is the case for the 250,000 veterans from the 1991 Persian Gulf War who suffer from Gulf War Illness (GWI). Our previous GWI research has focused on developing a model of GWI using organophosphate acetylcholinesterase inhibitors (OP AChEI, e.g. chemical warfare agents and pesticides) and exogenous corticosterone (CORT), to simulate high stress, in an effort to mimic several of the conditions experienced in theater and emulate the chronic neuroinflammation hypothesized to underlie GWI symptomology. In these studies, we uncovered a lack of correlation between OP AChEI-associated neuroinflammation and the levels of ACh or enzyme inhibition, suggesting that GWI and its associated neuroinflammation may result from the phosphorylation of other targets. Thus, an investigation into early phosphoprotein responses in the hippocampus and striatum was performed to better understand the signaling changes involved in this etiology. Using our validated mouse model, adult male C57BL/6J mice were exposed to CORT in the drinking water for 7 days followed by a single injection of diisopropyl fluorophosphate (DFP; 4.0 mg/kg, i.p.) on day 8. Mice were euthanized 30 min and 2 h post-injection via focused microwave irradiation. To evaluate region-specific effects, 20+ post-translationally modified protein targets were measured using multiplex ELISA (e.g., ERK1/2, GSK3, IkB-a, JNK, MEK1). To then optimize analysis of the specific data sets, a network parameter approach corresponding to radiality was used to assess the response of the phosphoprotein targets in relation to all other responses. This approach identified specific proteins (RPS6, CREB, p90RSK, and IkB-a) that were substantially activated or inhibited within the network, and is informative with regard to the mechanisms of interactions that are occurring as a result of this GWI exposure. These significant proteins suggest new potential biomolecular drivers and therapeutic targets of GWI symptomology. [Description provided by NIOSH]
• Subjects:
  Environmental Exposure Enzymes Immune System Insecticides Laboratories Nervous System Nervous System Diseases Occupational Health Phosphoric Acids Safety Toxicology

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• Keywords:
  Acetylcholinesterase Author Keywords: Organophosphates Chemical Warfare Agents Cholinesterase Inhibitors Chronic Inflammation Clinical Symptoms Dose Response ELISA Enzyme-linked Immunosorbent Assay Enzyme Inhibitors Exposure Assessment Exposure Levels Immune Reaction Laboratory Animals Laboratory Testing Neurological Disorders Neurological Reactions Neurological System Neurotoxicity Organophosphorus Compounds Pesticides Phosphates Proteins

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Maryland ; 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
• Pages in Document:
  72
• Volume:
  168
• Issue:
  1
• NIOSHTIC Number:
  nn:20055169
• Citation:
  Toxicologist 2019 Mar; 168(1)(Late-Breaking Suppl):72
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4)
• Federal Fiscal Year:
  2019
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 58th Annual Meeting and ToxExpo, March 10-14, 2019, Baltimore, Maryland
• Supplement:
  Late-Breaking Suppl
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:208c878775476f470b6fdf204c836cdf551b4f88079ceb181f73127ad7b2bf8b3d81169af9ae4ff8eb760d4f83281985424e406a4a81a58500bb484e15d20aea
• Download URL:
  https://stacks.cdc.gov/view/cdc/217529/cdc_217529_DS1.pdf
• File Type:
  [PDF - 586.05 KB ]