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

Frontiers in Neurology

Angela Boutté¹  Christina LaValle¹  Gary Kamimori¹  Jeffrey Nemes¹  Yongchao Ge²  Fatemeh Haghighi³  Caroline M. Wilson³  Zhaoyu Wang⁴  Walter Carr⁵ 

[1] Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States;Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States;Icahn School of Medicine at Mount Sinai, Nash Family Department of Neuroscience, New York, NY, United States;James J. Peters VA Medical Center, Medical Epigenetics, Bronx, NY, United States;Oak Ridge Institute for Science and Education, Oak Ridge, TN, United States;

关键词: blast exposure;    breacher;    epigenetics;    DNA methylation;    tinnitus;    sleep;   

DOI  :  10.3389/fneur.2020.01010

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown