The progression of radiation injury in a Wistar rat model of partial body irradiation with ∼5% bone marrow shielding

Beach, Tyler; Bakke, James; Riccio, Ed; Javitz, Harold S.; Nishita, Denise; Kapur, Shweta; Bunin, Deborah I.; Chang, Polly Y.

doi:10.1080/09553002.2023.2188937

Cited by 3 publications

(9 citation statements)

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“…For instance, in TBI C57BL6 mice circulating blood cell values are persistently reduced during the DEARE period for neutrophils, lymphocytes, red blood cells and platelets ( 4 ). In contrast, the PBI Wistar rat ( 15 ) and the L/J mouse model presented show increases in white blood cells, lymphocytes and neutrophils. It has been proposed that the persistent changes seen in the hematological compartment as delayed effect of irradiation may be the result of residual bone marrow damage (RBMD), as first described in the TBI C57BL6 ( 4 , 22 ) and more recently, other models ( 2 ).…”

Section: Discussionmentioning

confidence: 69%

“…Ruffled fur, hunched posture, and dehydration were the most common findings, and were reported as early as 1 day following irradiation. Malocclusions were also commonly observed as early as day 49; these have also been reported as a radiation associated finding in Wistar rats ( 15 ). Malocclusions were not observed in non-irradiated controls in either animal model.…”

Section: Resultsmentioning

confidence: 81%

“…The acute radiation response in the PBI BM2.5 C57L/J mouse model shows many characteristics common to TBI and PBI models of H- and GI-ARS in other strains of mice, in rats, and non-human primates. Leukocytopenia just days after irradiation is a common finding in TBI C57BL6 mice ( 16 ) and rhesus macaques ( 17 ), PBI C57BL6 ( 18 ), and C57 L/J ( 10 ) mice, Wistar rats ( 15 ) and rhesus macaques ( 19 , 20 ). In the PBI L/J model presented here, hematopoietic atrophy and gastrointestinal necrosis are clearly observed in the hematology values and histopathology tissues collected from ARS moribund mice ( Figure 6B ).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously published the results a similarly designed series of studies successfully describing the sequalae of ARS and DEARE in the PBI BM5 Wistar rat model ( 15 ). The studies described in this manuscript were performed at the same institution using the same equipment and following standard operating procedures (SOPs) and institutional practices.…”

Section: Introductionmentioning

confidence: 99%

“…The studies described in this manuscript were performed at the same institution using the same equipment and following standard operating procedures (SOPs) and institutional practices. Animal handling, clinical endpoints, and analytical methods were similar to those used described in Beach et al ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

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Delayed effects of radiation exposure in a C57L/J mouse model of partial body irradiation with ~2.5% bone marrow shielding

Beach,

Bakke,

McDonald

et al. 2024

Front. Public Health

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IntroductionMouse models of radiation injury are critical to the development of medical countermeasures (MCMs) against radiation. Now that MCMs against hematopoietic acute radiation syndrome (H-ARS) have achieved regulatory approval, attention is shifting to develop MCMs against the adverse effects of gastrointestinal acute radiation syndrome (GI-ARS) and delayed effects of acute radiation exposure (DEARE). The C57L/J mouse model of partial body irradiation (PBI) with 2.5% bone marrow shielding (BM2.5) is being leveraged to examine both GI-ARS and DEARE effects. Within days of PBI, mice may develop H- and GI-ARS followed several months later by DEARE as a multi-organ injury, which typically involves the lung and kidney (L- and K-DEARE, respectively). The objective of this manuscript is to describe the dose response relationship and progression of radiation injury in the C57L/J mouse and to evaluate its suitability for use in DEARE MCM testing.Materials and methodsIn two separate studies conducted over 2 years, male and female C57L/J mice were exposed to PBI BM2.5 with one hindlimb shielded from radiation, representing ~2.5% bone marrow shielding/sparing. Mice were X-ray irradiated at doses ranging from 9 to 13 Gy at 10 to 12 weeks of age for the purposes of assessing ARS survival at 30 days and DEARE survival at 182 days post-irradiation. Clinical indicators of ARS and DEARE were determined by clinical observations, body weights, hematology, clinical chemistry, magnetic resonance imaging (MRI) of lung, and histopathology of selected tissues.ResultsC57L/J mice developed canonical ARS responses of hematopoietic atrophy and gastrointestinal injury resulting in dose dependent mortality at doses ≥11 Gy between 1- and 15-days post-irradiation. In animals that survived ARS, DEARE associated mortality occurred in dose dependent fashion at ≥9 Gy for both sexes between 60- and 159-days post-irradiation with histopathology examinations indicating lung injury as the primary cause of death in moribund animals.ConclusionThe PBI BM2.5 C57L/J mouse model reliably produced known H- and GI-ARS effects at doses greater than those resulting in DEARE effects. Because of this, the C57L/J mouse can be used to test MCMs against L-DEARE injury, while avoiding ARS associated mortality.

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Section: Discussionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Delayed effects of radiation exposure in a C57L/J mouse model of partial body irradiation with ~2.5% bone marrow shielding

Beach,

Bakke,

McDonald

et al. 2024

Front. Public Health

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Impact of Partial Body Shielding from Very High Dose Rates on Untargeted Metabolomics in Biodosimetry

Pannkuk,

Laiakis,

Garty

et al. 2024

ACS Omega

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A realistic exposure to ionizing radiation (IR) from an improvised nuclear device will likely include individuals who are partially shielded from the initial blast delivered at a very high dose rate (VHDR). As different tissues have varying levels of radiosensitivity, e.g., hematopoietic vs gastrointestinal tissues, the effects of shielding on radiation biomarkers need to be addressed. Here, we explore how biofluid (urine and serum) metabolite signatures from male and female C57BL/6 mice exposed to VHDR (5−10 Gy/s) total body irradiation (TBI, 0, 4, and 8 Gy) compare to individuals exposed to partial body irradiation (PBI) (lower body irradiated [LBI] or upper body irradiated [UBI] at an 8 Gy dose) using a data-independent acquisition untargeted metabolomics approach. Although sex differences were observed in the spatial groupings of urine signatures from TBI and PBI mice, a metabolite signature (N6,N6,N6-trimethyllysine, carnitine, propionylcarnitine, hexosamine-valine-isoleucine, taurine, and creatine) previously developed from variable dose rate experiments was able to identify individuals with high sensitivity and specificity, irrespective of radiation shielding. A panel of serum metabolites composed from previous untargeted studies on nonhuman primates had excellent performance for separating irradiated cohorts; however, a multiomic approach to complement the metabolome could increase dose estimation confidence intervals. Overall, these results support the inclusion of small-molecule markers in biodosimetry assays without substantial interference from the upper or lower body shielding.

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Gastrointestinal Acute Radiation Syndrome: Mechanisms, Models, Markers, and Medical Countermeasures

Winters,

Marzella,

Molinar-Inglis

et al. 2024

Radiation Research

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There have been a number of reported human exposures to high dose radiation, resulting from accidents at nuclear power plants (e.g., Chernobyl), atomic bombings (Hiroshima and Nagasaki), and mishaps in industrial and medical settings. If absorbed radiation doses are high enough, evolution of acute radiation syndromes (ARS) will likely impact both the bone marrow as well as the gastrointestinal (GI) tract. Damage incurred in the latter can lead to nutrient malabsorption, dehydration, electrolyte imbalance, altered microbiome and metabolites, and impaired barrier function, which can lead to septicemia and death. To prepare for a medical response should such an incident arise, the National Institute of Allergy and Infectious Diseases (NIAID) funds basic and translational research to address radiation-induced GI-ARS, which remains a critical and prioritized unmet need. Areas of interest include identification of targets for damage and mitigation, animal model development, and testing of medical countermeasures (MCMs) to address GI complications resulting from radiation exposure. To appropriately model expected human responses, it is helpful to study analogous disease states in the clinic that resemble GI-ARS, to inform on best practices for diagnosis and treatment, and translate them back to inform nonclinical drug efficacy models. For these reasons, the NIAID partnered with two other U.S. government agencies (the Biomedical Advanced Research and Development Authority, and the Food and Drug Administration), to explore models, biomarkers, and diagnostics to improve understanding of the complexities of GI-ARS and investigate promising treatment approaches. A two-day workshop was convened in August 2022 that comprised presentations from academia, industry, healthcare, and government, and highlighted talks from 26 subject matter experts across five scientific sessions. This report provides an overview of information that was presented during the conference, and important discussions surrounding a broad range of topics that are critical for the research, development, licensure, and use of MCMs for GI-ARS.

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The progression of radiation injury in a Wistar rat model of partial body irradiation with ∼5% bone marrow shielding

Cited by 3 publications

References 20 publications

Delayed effects of radiation exposure in a C57L/J mouse model of partial body irradiation with ~2.5% bone marrow shielding

Delayed effects of radiation exposure in a C57L/J mouse model of partial body irradiation with ~2.5% bone marrow shielding

Impact of Partial Body Shielding from Very High Dose Rates on Untargeted Metabolomics in Biodosimetry

Gastrointestinal Acute Radiation Syndrome: Mechanisms, Models, Markers, and Medical Countermeasures

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