Spatiotemporal Phosphoprotein Signaling in a Mouse Model Using Corticosterone and Relevant Organophosphates

Details

• Personal Author:
  Boyd JW ; Kelly KA ; Michalovicz LT ; O'Callaghan JP ; Penatzer JA ; Prince N
• Description:
  Each year, 3 million people are exposed to organophosphates, contributing to approximately 300,000 deaths; many do not report appreciable acute effects immediately following exposure, 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). Previous GWI research has focused on models that dose with acetylcholinesterase (AChE) inhibitors (chemical warfare agents and pesticides) and exogenous corticosterone (CORT), to simulate high stress, in efforts to mimic chronic neuroinflammation associated with GWI symptomology. An investigation into early phosphoprotein responses in the cortex and striatum were performed to better understand the similarities of the early cellular changes involved in these etiologies. Using a 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.) or chlorpyrifos oxon (CPO; 8.0 mg/kg, i.p.) on day 8 and euthanized 30 min, 2 h, and 24 h post-injection via focused microwave irradiation. To evaluate brain-region-specific effects, 20+ post-translationally modified protein targets were measured using a multiplex ELISA (e.g., ERK1/2, IkB-a, JNK, MEK1) for both dosing regimens. Several phosphoprotein responses (ZAP70 and JNK) were found to be significantly increased (p<0.05) for CORT+CPO exposure, but not for CORT+DFP in both brain regions. Conversely, CREB and ERK were significantly phosphorylated for DFP exposures relative to CPO. This suggests the neuroinflammatory response in this mouse model may be driven by off-target mechanisms of AChE exposure. Further investigation of other relevant exposures and their phosphoprotein signaling effects must be performed to better understand potential biomolecular drivers of GWI-like symptomology. [Description provided by NIOSH]
• Subjects:
  Endocrine System Environmental Exposure Immune System Laboratories Nervous System Nervous System Diseases Occupational Health Phosphoric Acids Radiation Safety Steroids Toxicology

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• Keywords:
  Acetylcholinesterase Adrenal Cortex Brain Function Brain Matter Cell Signaling Cellular Reactions Chlorpyrifos Clinical Symptoms Corticosteroids Dose Response Etiology Exposure Assessment Exposure Levels Hormones Immune Reaction Irradiation Laboratory Animals Laboratory Testing Military Personnel Molecular Signaling Neurological Disorders Neurological Reactions Organophosphorus Compounds Phosphates Progesterone Proteins

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  California ; OSHA Region 3 ; OSHA Region 9 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  174
• Issue:
  1
• NIOSHTIC Number:
  nn:20058985
• Citation:
  Toxicologist 2020 Mar; 174(1):485
• CAS Registry Number:
  Chlorpyrifos (CAS RN 2921-88-2) ; Diisopropyl fluorophosphate (CAS RN 55-91-4)
• Federal Fiscal Year:
  2020
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 59th Annual Meeting and ToxExpo, March 15-19, 2020, Anaheim, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:5dbf4835032bbc299bc597a8147ff91a698ee8e8326da005d79bef4fa48835ecf04a46d26b7f0926f65757479c513ecee30e2cbdbef936a615219e0110fb746c
• Download URL:
  https://stacks.cdc.gov/view/cdc/223325/cdc_223325_DS1.pdf
• File Type:
  [PDF - 523.54 KB ]