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Explosive-driven double-blast exposure: molecular, histopathological, and behavioral consequences.

ABSTRACT: Traumatic brain injury generated by blast may induce long-term neurological and psychiatric sequelae. We aimed to identify molecular, histopathological, and behavioral changes in rats 2 weeks after explosive-driven double-blast exposure. Rats received two 30-psi (~?207-kPa) blasts 24 h apart or were handled identically without blast. All rats were behaviorally assessed over 2 weeks. At Day 15, rats were euthanized, and brains removed. Brains were dissected into frontal cortex, hippocampus, cerebellum, and brainstem. Western blotting was performed to measure levels of total-Tau, phosphorylated-Tau (pTau), amyloid precursor protein (APP), GFAP, Iba1, ?II-spectrin, and spectrin breakdown products (SBDP). Kinases and phosphatases, correlated with tau phosphorylation were also measured. Immunohistochemistry for pTau, APP, GFAP, and Iba1 was performed. pTau protein level was greater in the hippocampus, cerebellum, and brainstem and APP protein level was greater in cerebellum of blast vs control rats (p?

SUBMITTER: Murphy EK

PROVIDER: S-EPMC7566442 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Explosive-driven double-blast exposure: molecular, histopathological, and behavioral consequences.

Murphy Erin K EK Iacono Diego D Pan Hongna H Grimes Jamie B JB Parks Steven S Raiciulescu Sorana S Leonessa Fabio F Perl Daniel P DP

Scientific reports 20201015 1

Traumatic brain injury generated by blast may induce long-term neurological and psychiatric sequelae. We aimed to identify molecular, histopathological, and behavioral changes in rats 2 weeks after explosive-driven double-blast exposure. Rats received two 30-psi (~ 207-kPa) blasts 24 h apart or were handled identically without blast. All rats were behaviorally assessed over 2 weeks. At Day 15, rats were euthanized, and brains removed. Brains were dissected into frontal cortex, hippocampus, cereb ...[more]

PMID: 33060648

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Project description:Introduction:Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are two of the signature injuries in military service members who have been exposed to explosive blasts during deployments to Iraq and Afghanistan. Acute stress disorder (ASD), which occurs within 2-30 d after trauma exposure, is a more immediate psychological reaction predictive of the later development of PTSD. Most previous studies have evaluated service members after their return from deployment, which is often months or years after the initial blast exposure. The current study is the first large study to collect psychological and neuropsychological data from active duty service members within a few days after blast exposure. Materials and Methods:Recruitment for blast-injured TBI patients occurred at the Air Force Theater Hospital, 332nd Air Expeditionary Wing, Joint Base Balad, Iraq. Patients were referred from across the combat theater and evaluated as part of routine clinical assessment of psychiatric and neuropsychological symptoms after exposure to an explosive blast. Four measures of neuropsychological functioning were used: the Military Acute Concussion Evaluation (MACE); the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS); the Headminder Cognitive Stability Index (CSI); and the Automated Neuropsychological Assessment Metrics, Version 4.0 (ANAM4). Three measures of combat exposure and psychological functioning were used: the Combat Experiences Scale (CES); the PTSD Checklist-Military Version (PCL-M); and the Acute Stress Disorder Scale (ASDS). Assessments were completed by a deployed clinical psychologist, clinical social worker, or mental health technician. Results:A total of 894 patients were evaluated. Data from 93 patients were removed from the data set for analysis because they experienced a head injury due to an event that was not an explosive blast (n = 84) or they were only assessed for psychiatric symptoms (n = 9). This resulted in a total of 801 blast-exposed patients for data analysis. Because data were collected in-theater for the initial purpose of clinical evaluation, sample size varied widely between measures, from 565 patients who completed the MACE to 154 who completed the CES. Bivariate correlations revealed that the majority of psychological measures were significantly correlated with each other (ps ? 0.01), neuropsychological measures were correlated with each other (ps ? 0.05), and psychological and neuropsychological measures were also correlated with each other (ps ? 0.05). Conclusions:This paper provides one of the first descriptions of psychological and neuropsychological functioning (and their inter-correlation) within days after blast exposure in a large sample of military personnel. Furthermore, this report describes the methodology used to gather data for the acute assessment of TBI, PTSD, and ASD after exposure to an explosive blast in the combat theater. Future analyses will examine the common and unique symptoms of TBI and PTSD, which will be instrumental in developing new assessment approaches and intervention strategies.

Project description: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, low-level 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.

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Explosive-driven double-blast exposure: molecular, histopathological, and behavioral consequences.

Publications

Explosive-driven double-blast exposure: molecular, histopathological, and behavioral consequences.

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