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DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters

Background: Injuries from exposure to explosions rose dramatically during the Iraq and Afghanistan wars, which motivated investigation of blast-related neurotrauma. We have undertaken human studies involving military “breachers” —exposed to controlled, low-level blast during a 3-days explosive breac...

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Autores principales: Wang, Zhaoyu, Wilson, Caroline M., Ge, Yongchao, Nemes, Jeffrey, LaValle, Christina, Boutté, Angela, Carr, Walter, Kamimori, Gary, Haghighi, Fatemeh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645105/
https://www.ncbi.nlm.nih.gov/pubmed/33192958
http://dx.doi.org/10.3389/fneur.2020.01010
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author Wang, Zhaoyu
Wilson, Caroline M.
Ge, Yongchao
Nemes, Jeffrey
LaValle, Christina
Boutté, Angela
Carr, Walter
Kamimori, Gary
Haghighi, Fatemeh
author_facet Wang, Zhaoyu
Wilson, Caroline M.
Ge, Yongchao
Nemes, Jeffrey
LaValle, Christina
Boutté, Angela
Carr, Walter
Kamimori, Gary
Haghighi, Fatemeh
author_sort Wang, Zhaoyu
collection PubMed
description Background: Injuries from exposure to explosions rose dramatically during the Iraq and Afghanistan wars, which motivated investigation of blast-related neurotrauma. We have undertaken human studies involving military “breachers” —exposed to controlled, low-level blast during a 3-days explosive breaching course. Methods: We screened epigenetic profiles in peripheral blood samples from 59 subjects (in two separate U.S. Military training sessions) using Infinium MethylationEPIC BeadChips. Participants had varying numbers of exposures to blast over their military careers (empirically defined as high ≥ 40, and conversely, low < 39 breaching exposures). Daily self-reported physiological symptoms were recorded. Tinnitus, memory problems, headaches, and sleep disturbances are most frequently reported. Results: We identified 14 significantly differentially methylated regions (DMRs) within genes associated with cumulative blast exposure in participants with high relative to low cumulative blast exposure. Notably, NTSR1 and SPON1 were significantly differentially methylated in high relative to low blast exposed groups, suggesting that sleep dysregulation may be altered in response to chronic cumulative blast exposure. In comparing lifetime blast exposure at baseline (prior to exposure in current training), and top associated symptoms, we identified significant DMRs associated with tinnitus, sleep difficulties, and headache. Notably, we identified KCNN3, SOD3, MUC4, GALR1, and WDR45B, which are implicated in auditory function, as differentially methylated associated with self-reported tinnitus. These findings suggest neurobiological mechanisms behind auditory injuries in our military warfighters and are particularly relevant given tinnitus is not only a primary disability among veterans, but has also been demonstrated in active duty medical records for populations exposed to blast in training. Additionally, we found that differentially methylated regions associated with the genes CCDC68 and COMT track with sleep difficulties, and those within FMOD and TNXB track with pain and headache. Conclusion: Sleep disturbances, as well as tinnitus and chronic pain, are widely reported in U.S. military service members and veterans. As we have previously demonstrated, DNA methylation encapsulates lifetime exposure to blast. The current data support previous findings and recapitulate transcriptional regulatory alterations in genes involved in sleep, auditory function, and pain. These data uncovered novel epigenetic and transcriptional regulatory mechanism underlying the etiological basis of these symptoms.
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spelling pubmed-76451052020-11-13 DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters Wang, Zhaoyu Wilson, Caroline M. Ge, Yongchao Nemes, Jeffrey LaValle, Christina Boutté, Angela Carr, Walter Kamimori, Gary Haghighi, Fatemeh Front Neurol Neurology Background: Injuries from exposure to explosions rose dramatically during the Iraq and Afghanistan wars, which motivated investigation of blast-related neurotrauma. We have undertaken human studies involving military “breachers” —exposed to controlled, low-level blast during a 3-days explosive breaching course. Methods: We screened epigenetic profiles in peripheral blood samples from 59 subjects (in two separate U.S. Military training sessions) using Infinium MethylationEPIC BeadChips. Participants had varying numbers of exposures to blast over their military careers (empirically defined as high ≥ 40, and conversely, low < 39 breaching exposures). Daily self-reported physiological symptoms were recorded. Tinnitus, memory problems, headaches, and sleep disturbances are most frequently reported. Results: We identified 14 significantly differentially methylated regions (DMRs) within genes associated with cumulative blast exposure in participants with high relative to low cumulative blast exposure. Notably, NTSR1 and SPON1 were significantly differentially methylated in high relative to low blast exposed groups, suggesting that sleep dysregulation may be altered in response to chronic cumulative blast exposure. In comparing lifetime blast exposure at baseline (prior to exposure in current training), and top associated symptoms, we identified significant DMRs associated with tinnitus, sleep difficulties, and headache. Notably, we identified KCNN3, SOD3, MUC4, GALR1, and WDR45B, which are implicated in auditory function, as differentially methylated associated with self-reported tinnitus. These findings suggest neurobiological mechanisms behind auditory injuries in our military warfighters and are particularly relevant given tinnitus is not only a primary disability among veterans, but has also been demonstrated in active duty medical records for populations exposed to blast in training. Additionally, we found that differentially methylated regions associated with the genes CCDC68 and COMT track with sleep difficulties, and those within FMOD and TNXB track with pain and headache. Conclusion: Sleep disturbances, as well as tinnitus and chronic pain, are widely reported in U.S. military service members and veterans. As we have previously demonstrated, DNA methylation encapsulates lifetime exposure to blast. The current data support previous findings and recapitulate transcriptional regulatory alterations in genes involved in sleep, auditory function, and pain. These data uncovered novel epigenetic and transcriptional regulatory mechanism underlying the etiological basis of these symptoms. Frontiers Media S.A. 2020-10-23 /pmc/articles/PMC7645105/ /pubmed/33192958 http://dx.doi.org/10.3389/fneur.2020.01010 Text en Copyright © 2020 Wang, Wilson, Ge, Nemes, LaValle, Boutté, Carr, Kamimori and Haghighi. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Wang, Zhaoyu
Wilson, Caroline M.
Ge, Yongchao
Nemes, Jeffrey
LaValle, Christina
Boutté, Angela
Carr, Walter
Kamimori, Gary
Haghighi, Fatemeh
DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters
title DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters
title_full DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters
title_fullStr DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters
title_full_unstemmed DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters
title_short DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters
title_sort dna methylation patterns of chronic explosive breaching in u.s. military warfighters
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645105/
https://www.ncbi.nlm.nih.gov/pubmed/33192958
http://dx.doi.org/10.3389/fneur.2020.01010
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