A pilot reverse virtual screening study suggests toxic exposures caused long-term epigenetic changes in Gulf War Illness
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 age...
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| Format: | Article |
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Elsevier
2022-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022005013 |
| _version_ | 1797978183501348864 |
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| author | Modeline Jean-Pierre Lindsay T. Michalovicz Kimberly A. Kelly James P. O'Callaghan Lubov Nathanson Nancy Klimas Travis J. A. Craddock |
| author_facet | Modeline Jean-Pierre Lindsay T. Michalovicz Kimberly A. Kelly James P. O'Callaghan Lubov Nathanson Nancy Klimas Travis J. A. Craddock |
| author_sort | Modeline Jean-Pierre |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T05:18:55Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:18:55Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-d82e839dc6404e678b6e114c099f4bf92022-12-24T04:55:04ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012062066213A pilot reverse virtual screening study suggests toxic exposures caused long-term epigenetic changes in Gulf War IllnessModeline Jean-Pierre0Lindsay T. Michalovicz1Kimberly A. Kelly2James P. O'Callaghan3Lubov Nathanson4Nancy Klimas5Travis J. A. Craddock6Department of Psychology & Neuroscience, Nova Southeastern University, Ft. Lauderdale, FL, United States; Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, United StatesHealth Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV, United StatesHealth Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV, United StatesHealth Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV, United StatesInstitute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, United States; Department of Clinical Immunology, Nova Southeastern University, Ft. Lauderdale, FL, United StatesInstitute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, United States; Department of Clinical Immunology, Nova Southeastern University, Ft. Lauderdale, FL, United States; Miami Veterans Affairs Medical Center, Miami, FL, United StatesDepartment of Psychology & Neuroscience, Nova Southeastern University, Ft. Lauderdale, FL, United States; Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, United States; Department of Clinical Immunology, Nova Southeastern University, Ft. Lauderdale, FL, United States; Department of Computer Science, Nova Southeastern University, Ft. Lauderdale, FL, United States; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2001037022005013Gulf war illnessPesticidesReverse screeningToxicologyTarget identificationDNA methylation |
| spellingShingle | Modeline Jean-Pierre Lindsay T. Michalovicz Kimberly A. Kelly James P. O'Callaghan Lubov Nathanson Nancy Klimas Travis J. A. Craddock A pilot reverse virtual screening study suggests toxic exposures caused long-term epigenetic changes in Gulf War Illness Computational and Structural Biotechnology Journal Gulf war illness Pesticides Reverse screening Toxicology Target identification DNA methylation |
| title | A pilot reverse virtual screening study suggests toxic exposures caused long-term epigenetic changes in Gulf War Illness |
| title_full | A pilot reverse virtual screening study suggests toxic exposures caused long-term epigenetic changes in Gulf War Illness |
| title_fullStr | A pilot reverse virtual screening study suggests toxic exposures caused long-term epigenetic changes in Gulf War Illness |
| title_full_unstemmed | A pilot reverse virtual screening study suggests toxic exposures caused long-term epigenetic changes in Gulf War Illness |
| title_short | A pilot reverse virtual screening study suggests toxic exposures caused long-term epigenetic changes in Gulf War Illness |
| title_sort | pilot reverse virtual screening study suggests toxic exposures caused long term epigenetic changes in gulf war illness |
| topic | Gulf war illness Pesticides Reverse screening Toxicology Target identification DNA methylation |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022005013 |
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