A Pilot Reverse Virtual Screening Study Suggests Toxic Exposures Caused Long-Term Epigenetic Changes in Gulf War Illness

Details

• Personal Author:
  Craddock TJA ; Jean-Pierre M ; Kelly KA ; Klimas N ; Michalovicz LT ; Nathanson L ; O'Callaghan JP
• Description:
  Gulf War Illness (GWI) is a chronic illness that affects upward of 32% of deployed Veterans to the 1991 Gulf War (GW). The symptoms are medically unexplained, ranging across cognitive deficits, fatigue, gastrointestinal problems, and musculoskeletal pain. Research indicates that chemical warfare agents play a key role in the onset and progression of GWI. The Khamisiyah ammunition storage that housed chemical warfare agents such as sarin, an acetylcholinesterase (AChE) inhibitor, was demolished during the GW, releasing toxicants into the atmosphere affecting deployed troops. Exposure to other chemical agents such as pyridostigmine bromide, N,N-diethyl-m-toluamide, permethrin and chlorpyrifos, were also prevalent during the war. These additional chemical agents have also been shown to inhibit AChE. AChE inhibition induces an acetylcholine build-up, disrupting signals between nerves and muscles, which in high doses leads to asphyxiation. Little is known about low dose exposure. As bioactive compounds tend to interact with multiple proteins with various physiological effect, we aimed to identify other potential shared targets to understand the extent in which these chemicals could lead to GWI. We followed a reverse screening approach where each chemical is computationally docked to a library of protein targets. The programs PharmMapper and TargetNet were used for this purpose, and further analyses were conducted to mark significant changes in participants with GWI. Previously published work on DNA methylation status in GWI was reanalyzed focusing specifically on the predicted shared targets indicating significant changes in DNA methylation of the associated genes. Our findings thus suggest that exposure to GWI-related agents may converge on similar targets with roles in inflammation, neurotransmitter and lipid metabolism, and detoxification which may have impacts on neurodegenerative-like disease and oxidative stress in Veterans with GWI. [Description provided by NIOSH]
• Subjects:
  Genetics Insecticides Musculoskeletal System Nervous System Occupational Health Safety Toxicology
• Keywords:
  Acetylcholinesterase Author Keywords: Gulf War Illness Chemical Warfare Agents DNA Damage DNA Methylation Genes Military Personnel Muscles Nerves Neurotransmitters Oxidative Stress Pesticides Reverse Screening Sarin Target Identification Toxic Effects

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• ISSN:
  2001-0370
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Florida ; OSHA Region 3 ; OSHA Region 4 ; 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:
  20
• NIOSHTIC Number:
  nn:20066527
• Citation:
  Comput Struct Biotechnol J 2022 Dec; 20:6206-6213
• Contact Point Address:
  Modeline Jean-Pierre, Department of Psychology & Neuroscience, Nova Southeastern University, Ft. Lauderdale, FL, United States
• Email:
  mj1333@mynsu.nova.edu
• Federal Fiscal Year:
  2023
• Peer Reviewed:
  True
• Source Full Name:
  Computational and Structural Biotechnology Journal
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:b0267f073d1967f0d1ca6afe0ee6b7ab25b5ae6c28b02dea3965c177ee14a01689888cec67c688b6e1c9de427395606c8c0c0299fae794f493469a3eb9767098
• Download URL:
  https://stacks.cdc.gov/view/cdc/231108/cdc_231108_DS1.pdf
• File Type:
  [PDF - 1.06 MB ]