Lung transcriptome of nonhuman primates exposed to total- and partial-body irradiation

Vellichirammal, Neetha Nanoth; Sethi, Sahil; Pandey, Sanjit; Singh, Jatinder; Wise, Stephen Y.; Carpenter, Alana D.; Fatanmi, Oluseyi O.; Guda, Chittibabu; Singh, Vijay K.

doi:10.1016/j.omtn.2022.08.006

Cited by 18 publications

(8 citation statements)

References 80 publications

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“…In another study conducted in C57BL/6 mice, it was found that surviving males appeared to have elevated levels of inflammasome genes which may contribute to the survival of these animals [Brickey et al, 2022]. In nonhuman primates, diversity was observed in estrogen receptor signaling and differential expression of genes in the jejunum when comparing sex and countermeasure treatment in total and partial body irradiation (PBI) models [Vellichirammal et al, 2023]. A recent study in human patients undergoing myeloablative TBI revealed a panel of 4 differential expressed metabolites, namely, phosphatidylcholine, urate, ornithine, and glycochenodeoxycholate-3-sulfate [Hong et al, 2023].…”

Section: Introductionmentioning

confidence: 99%

Sex as a Factor in Murine Radiation Research: Implications for Countermeasure Development

Holmes-Hampton,

Kumar,

Valenzia

et al. 2023

Cytogenet Genome Res

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There is an increased threat of exposure to ionizing radiation, in the event of such exposure the availability of medical countermeasures will be vital to ensure the protection of the population. Effective countermeasures should be efficacious across a varied population and most importantly amongst both males and females. Radiation research must be conducted in animal models which act as a surrogate for the human response. Here we identify differences in survival in male and female C57BL/6 in both a total body irradiation (TBI) model using the Armed Forces Radiobiology Research Institute (AFRRI) 60Co source and a partial body irradiation (PBI) model using the AFRRI Linear Accelerator (LINAC) with 4MV photons and 2.5% bone marrow shielding. In both models we observed a higher degree of radioresistance in female animals and a corresponding radiosensitivity in males. One striking difference in male and female rodents is body size/weight and we investigated the role of pre-irradiation body weight on survivability for animals irradiated at the same dose of irradiation (8 Gy TBI, 14 Gy PBI). We found that weight does not influence survival in the TBI model and that heavier males but lighter females have increased survival in the PBI model. This incongruence in survival amongst the sexes should be taken into consideration in the course of developing radiation countermeasures for response to a mass casualty incident.

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Section: Introductionmentioning

confidence: 99%

Sex as a Factor in Murine Radiation Research: Implications for Countermeasure Development

Holmes-Hampton,

Kumar,

Valenzia

et al. 2023

Cytogenet Genome Res

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“…We have also shown that both GT3 and tetrahydrobiopterin supplementation reduce vascular peroxynitrite production following radiation ( 77 ). In addition, GT3 modulated irradiation-induced transcriptomic changes ( 53 ) and most importantly showed promising hematopoietic recovery in NHP models by stimulating/preserving the regenerating ability of the HSCs ( 34 , 40 ). Here, we report that PBI doses of 4 and 5.8 Gy resulted in a marginal reduction in circulating neutrophils and platelets levels, including decreased reticulocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Anterior/posterior measurements of the NHPs at the location of the absorbed dose target (“core of the abdomen”) were measured with a digital caliper. Irradiation procedures with LINAC, dose rate, and dosimetry have been described in detail earlier ( 53 ).…”

Section: Methodsmentioning

confidence: 99%

Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation

Garg,

Miousse

et al. 2023

Radiation Research

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Currently, no radioprotectors have been approved to mitigate hematopoietic injury after exposure to ionizing radiation. Acute ionizing radiation results in damage to both hematopoietic and immune system cells. Pre-exposure prophylactic agents are needed for first responders and military personnel. In this study, the ability of gamma-tocotrienol (GT3), a promising radioprotector and antioxidant, to ameliorate partial-body radiation-induced damage to the hematopoietic compartment was evaluated in a nonhuman primate (NHP) model. A total of 15 rhesus NHPs were divided into two groups, and were administered either GT3 or vehicle 24 h prior to 4 or 5.8 Gy partial-body irradiation (PBI), with 5% bone marrow (BM) sparing. Each group consisted of four NHPs, apart from the vehicle-treated group exposed to 5.8 Gy, which had only three NHPs. BM samples were collected 8 days prior to irradiation in addition to 2, 7, 14, and 30 days postirradiation. To assess the clonogenic ability of hematopoietic stem and progenitor cells (HSPCs), colony forming unit (CFU) assays were performed, and lymphoid cells were immunophenotyped using flow cytometry. As a result of GT3 treatment, an increase in HSPC function was evident by an increased recovery of CFU-granulocyte macrophages (CFU-GM). Additionally, GT3 treatment was shown to increase the percentage of CD34+ cells, including T and NK-cell subsets. Our data further affirm GT3’s role in hematopoietic recovery and suggest the need for its further development as a prophylactic radiation medical countermeasure.

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“…GT3 is a radiation countermeasure for H-ARS and has limited effects against a supralethal dose of radiation inducing GI-ARS. We have also conducted a transcriptomic study, and in that study there was also limited effects of GT3, but the supralethal radiation dose demonstrated significant transcriptomic changes [ 40 ]. This study was undertaken to investigate the potential of GT3 in accelerating GI recovery in NHPs receiving PBI at a dose of 12 Gy with 5% sparing of BM.…”

Section: Discussionmentioning

confidence: 99%

“…Anterior/posterior (AP) measurements of the NHPs at the location of the absorbed dose target (“core of the abdomen”) were obtained with a digital caliper. Irradiation procedures with LINAC and dosimetry have been described previously [ 40 ].…”

Section: Methodsmentioning

confidence: 99%

Effects of Gamma-Tocotrienol on Partial-Body Irradiation-Induced Intestinal Injury in a Nonhuman Primate Model

Garg

Miousse

et al. 2022

Antioxidants

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Exposure to high doses of radiation, accidental or therapeutic, often results in gastrointestinal (GI) injury. To date, there are no therapies available to mitigate GI injury after radiation exposure. Gamma-tocotrienol (GT3) is a promising radioprotector under investigation in nonhuman primates (NHP). We have shown that GT3 has radioprotective function in intestinal epithelial and crypt cells in NHPs exposed to 12 Gy total-body irradiation (TBI). Here, we determined GT3 potential in accelerating the GI recovery in partial-body irradiated (PBI) NHPs using X-rays, sparing 5% bone marrow. Sixteen rhesus macaques were treated with either vehicle or GT3 24 h prior to 12 Gy PBI. Structural injuries and crypt survival were examined in proximal jejunum on days 4 and 7. Plasma citrulline was assessed using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Crypt cell proliferation and apoptotic cell death were evaluated using Ki-67 and TUNEL staining. PBI significantly decreased mucosal surface area and reduced villous height. Interestingly, GT3 increased crypt survival and enhanced stem cell proliferation at day 4; however, the effects seemed to be minimized by day 7. GT3 did not ameliorate a radiation-induced decrease in citrulline levels. These data suggest that X-rays induce severe intestinal injury post-PBI and that GT3 has minimal radioprotective effect in this novel model.

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Lung transcriptome of nonhuman primates exposed to total- and partial-body irradiation

Cited by 18 publications

References 80 publications

Sex as a Factor in Murine Radiation Research: Implications for Countermeasure Development

Sex as a Factor in Murine Radiation Research: Implications for Countermeasure Development

Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation

Effects of Gamma-Tocotrienol on Partial-Body Irradiation-Induced Intestinal Injury in a Nonhuman Primate Model

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