A Moderate Blast Exposure Results in Dysregulated Gene Network Activity Related to Cell Death, Survival, Structure, and Metabolism

Abstract

Blast exposure is common in military personnel during training and combat operations, yet biological mechanisms related to cell survival and function that coordinate recovery remain poorly understood. This study explored how moderate blast exposure influences gene expression; specifically, gene-network changes following moderate blast exposure. On day 1 (baseline) of a 10-day military training program, blood samples were drawn, and health and demographic information collected. Helmets equipped with bilateral sensors worn throughout training measured overpressure in pounds per square inch (psi). On day 7, some participants experienced moderate blast exposure (peak pressure ≥5 psi). On day 10, 3 days post-exposure, blood was collected and compared to baseline with RNA-sequencing to establish gene expression changes. Based on dysregulation data from RNA-sequencing, followed by top gene networks identified with Ingenuity Pathway Analysis, a subset of genes was validated (NanoString). Five gene networks were dysregulated; specifically, two highly significant networks: (1) Cell Death and Survival (score: 42), including 70 genes, with 50 downregulated and (2) Cell Structure, Function, and Metabolism (score: 41), including 69 genes, with 41 downregulated. Genes related to ubiquitination, including neuronal development and repair: UPF1, RNA Helicase and ATPase (UPF1) was upregulated while UPF3 Regulator of Nonsense Transcripts Homolog B (UPF3B) was downregulated. Genes related to inflammation were upregulated, including AKT serine/threonine kinase 1 (AKT1), a gene coordinating cellular recovery following TBIs. Moderate blast exposure induced significant gene expression changes including gene networks involved in (1) cell death and survival and (2) cellular development and function. The present findings may have implications for understanding blast exposure pathology and subsequent recovery efforts.

Association of MOS-Based Blast Exposure With Medical Outcomes

“…The anecdotally reported occupational blast-related symptomology has been supported by a symptom survey among a blast-exposed professional community (3), by pilot study evidence that included cognitive performance and blood-based neurotrauma biomarkers collected during training programs involving explosives (4), and by symptom inventory in other field studies of operational training (5)(6)(7)(8)(9). In addition to symptom reporting, research observations of low-level blast-associated effects have included deficits in cognitive function (10), cellular changes in peripheral blood (11)(12)(13)(14)(15), and neuroimaging evidence that blast exposure may negatively affect neurophysiological functioning in simple tasks requiring memory of visual stimuli (6). It is important to note that none of these cited studies included blast exposure association with diagnosed injury-the focus was on blast exposures considered low level in magnitude.…”

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

“…Based on concerns for potential injury by the cadre of breachers and instructors, the Department of Defense (DOD) has been conducting studies on the bio-effects from repeated exposure, and findings from our own group (21) and others (22,23) have begun to show that blast exposure during training is capable of inducing changes in DNA methylation and gene expression in military breachers (22) that track with the physiological symptoms of blast injury (24). In the present study of military breachers, we set out to replicate previous findings, investigating effects of acute and chronic blast exposure on DNA methylation and reported symptoms at baseline across two military training sites-representing the largest DNA methylation study of breachers to date.…”

The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression

“…Finally, Trip12 is an E3 ubiquitin ligase with rare loss-of-function mutations implicated in cognitive deficits and autism [ 80 ]. Trip12 expression is elevated in human blood samples after controlled exposure to moderate blast in vivo [ 81 ]. Trip12 has 3 known phospho-sites and 76 interactors; however, its mechanistic role in LIB-induced cognitive deficits in rTg4510 remain unclear.…”