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Effect of Sex on Biomarker Response in a Mouse Model of the Hematopoietic Acute Radiation Syndrome.

ABSTRACT: Sex is an important confounding variable in biomarker development that must be incorporated into biomarker discovery and validation. Additionally, understanding of sex as a biological variable is essential for effective translation of biomarkers in animal models to human populations. Toward these ends, we conducted high-throughput targeted metabolomics using liquid chromatography tandem mass spectrometry and multiplexed immunoassay analyses using a Luminex-based system in both male and female mice in a model of total-body irradiation at a radiation dose consistent with the hematopoietic acute radiation syndrome. Metabolomic and immunoassay analyses identified metabolites and cytokines that were significantly different in plasma from naive and irradiated C57BL/6 mice consisting of equal numbers of female and male mice at 3 d after 8.0 or 8.72 Gy, an approximate LD60-70/30 dose of total-body irradiation. An additional number of metabolites and cytokines had sex-specific responses after radiation. Analyses of sham-irradiated mice illustrate the presence of stress-related changes in several cytokines due simply to undergoing the irradiation procedure, absent actual radiation exposure. Basal differences in metabolite levels between female and male were also identified as well as time-dependent changes in cytokines up to 9 d postexposure. These studies provide data toward defining the influence of sex on plasma-based biomarker candidates in a well-defined mouse model of acute radiation syndrome.

SUBMITTER: Jones JW

PROVIDER: S-EPMC6384137 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Effect of Sex on Biomarker Response in a Mouse Model of the Hematopoietic Acute Radiation Syndrome.

Jones Jace W JW Alloush Jenna J Sellamuthu Rajendran R Chua Hui Lin HL MacVittie Thomas J TJ Orschell Christie M CM Kane Maureen A MA

Health physics 20190401 4

Sex is an important confounding variable in biomarker development that must be incorporated into biomarker discovery and validation. Additionally, understanding of sex as a biological variable is essential for effective translation of biomarkers in animal models to human populations. Toward these ends, we conducted high-throughput targeted metabolomics using liquid chromatography tandem mass spectrometry and multiplexed immunoassay analyses using a Luminex-based system in both male and female mi ...[more]

PMID: 30681425

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Project description:Intensive research is underway to find new agents that can successfully mitigate the acute effects of radiation exposure. This is primarily in response to potential counterthreats of radiological terrorism and nuclear accidents but there is some hope that they might also be of value for cancer patients treated with radiation therapy. Research into mitigation countermeasures typically employs classic animal models of acute radiation syndromes (ARS) that develop after whole-body irradiation (WBI). While agents are available that successfully mitigate ARS when given after radiation exposure, their success raises questions as to whether they simply delay lethality or unmask potentially lethal radiation pathologies that may appear later in time. Life shortening is a well-known consequence of WBI in humans and experimental animals, but it is not often examined in a mitigation setting and its causes, other than cancer, are not well-defined. This is in large part because delayed effects of acute radiation exposure (DEARE) do not follow the strict time-dose phenomena associated with ARS and present as a diverse range of symptoms and pathologies with low mortality rates that can be evaluated only with the use of large cohorts of subjects, as in this study. Here, we describe chronically increased mortality rates up to 660 days in large numbers of mice given LD70/30 doses of WBI. Systemic myeloid cell activation after WBI persists in some mice and is associated with late immunophenotypic changes and hematopoietic imbalance. Histopathological changes are largely of a chronic inflammatory nature and variable incidence, as are the clinical symptoms, including late diarrhea that correlates temporally with changes in the content of the microbiome. We also describe the acute and long-term consequences of mitigating hematopoietic ARS (H-ARS) lethality after LD70/30 doses of WBI in multiple cohorts of mice treated uniformly with radiation mitigators that have a common 4-nitro-phenylsulfonamide (NPS) pharmacophore. Effective NPS mitigators dramatically decrease ARS mortality. There is slightly increased subacute mortality, but the rate of late mortalities is slowed, allowing some mice to live a normal life span, which is not the case for WBI controls. The study has broad relevance to radiation late effects and their potential mitigation and epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis.

Project description:BACKGROUND:Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss, and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. METHODS:Human MSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24, and 48?h after lethal whole-body irradiation (10?Gy). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3), and in vivo permeability to 4?kDa FITC-labeled dextran. Renewal of the small intestinal epithelium was determined by quantifying epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using Kaplan-Meier and Cox methods. RESULTS:We demonstrated that MSC-derived extracellular vesicle treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10?Gy whole-body irradiation and so increased their survival time. This effect could be attributed to the efficacy of MSC-derived extracellular vesicles in reducing mucosal barrier disruption. We showed that the MSC-derived extracellular vesicles improved the renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. The MSC-derived extracellular vesicles also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium. CONCLUSIONS:MSC-derived extracellular vesicles promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived extracellular vesicles could be an effective therapy for limiting acute radiation syndrome.

Dataset Information

Effect of Sex on Biomarker Response in a Mouse Model of the Hematopoietic Acute Radiation Syndrome.

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Effect of Sex on Biomarker Response in a Mouse Model of the Hematopoietic Acute Radiation Syndrome.

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