Acute and Chronic Molecular Signatures and Associated Symptoms of Blast Exposure in Military Breachers

Abstract

Injuries from exposure to explosions rose dramatically during the Iraq and Afghanistan wars, which motivated investigations of blast-related neurotrauma and operational breaching. In this study, military ''breachers'' were exposed to controlled, lowlevel blast during a 10-day explosive breaching course. Using an omics approach, we assessed epigenetic, transcriptional, and inflammatory profile changes in blood from operational breaching trainees, with varying levels of lifetime blast exposure, along with daily self-reported symptoms (with tinnitus, headaches, and sleep disturbances as the most frequently reported). Although acute exposure to blast did not confer epigenetic changes, specifically in DNA methylation, differentially methylated regions (DMRs) with coordinated gene expression changes associated with lifetime cumulative blast exposures were identified. The accumulative effect of blast showed increased methylation of PAX8 antisense transcript with coordinated repression of gene expression, which has been associated with sleep disturbance. DNA methylation analyses conducted in conjunction with reported symptoms of tinnitus in the low versus high blast incidents groups identified DMRS in KCNE1 and CYP2E1 genes. KCNE1 and CYP2E1 showed the expected inverse correlation between DNA methylation and gene expression, which have been previously implicated in noise-related hearing loss. Although no significant transcriptional changes were observed in samples obtained at the onset of the training course relative to chronic cumulative blast, we identified a large number of transcriptional perturbations acutely pre-versus post-blast exposure. Acutely, 67 robustly differentially expressed genes (fold change ‡1.5), including UFC1 and YOD1 ubiquitin-related proteins, were identified. Inflammatory analyses of cytokines and chemokines revealed dysregulation of MCP-1, GCSF, HGF, MCSF, and RANTES acutely after blast exposure. These data show the importance of an omics approach, revealing that transcriptional and inflammatory biomarkers capture acute low-level blast overpressure exposure, whereas DNA methylation marks encapsulate chronic long-term symptoms.

Hearing Loss and Irritability Reporting Without Vestibular Differences in Explosive Breaching Professionals

“…As such, the sample size for this study may limit the power of these results and should be interpreted with some caution. However, these findings are consistent with other recent work ( 18 , 19 ), though it should be noted that breachers did not report headaches at a higher rate. In addition, self-reported responses are subjective and can be influenced by motivation to be perceived by others as ill or injured, or actually being perceived as such.…”

Association of MOS-Based Blast Exposure With Medical Outcomes

“…Assays of periodically collected biological samples in the Department of Defense Serum Repository could play a similar role. Although physiological markers of low-level blast exposure have been elusive ( 7 ), there is emerging evidence that blood-based assays among personnel with a history of exposure to blast shows epigenetic differences from comparable personnel who do not have history of blast exposure ( 27 ). At minimum, the exploratory research design employed here with Soldiers could be replicated with comparable US Marine Corps populations.…”

Expression of GFAP and Tau Following Blast Exposure in the Cerebral Cortex of Ferrets

“…The effects of exposure to blast in people are cumulative and persistent (1,2). Blasts can cause damage that involves blood vessels, brain parenchyma, and white matter among other structures (3).…”