Longitudinal multi-omic changes in the transcriptome and proteome of peripheral blood cells after a 4 Gy total body radiation dose to Rhesus macaques

Abstract

Background: Non-human primates, such as Rhesus macaques, are a powerful model for studies of the cellular and physiological effects of radiation, development of radiation biodosimetry, and for understanding the impact of radiation on human health. Here, we study the effects of 4 Gy total body irradiation (TBI) at the molecular level out to 28 days and at the cytogenetic level out to 56 days after exposure. We combine the global transcriptomic and proteomic responses in peripheral whole blood to assess the impact of acute TBI exposure at extended times post irradiation. Results: The overall mRNA response in the first week reflects a strong inflammatory reaction, infection response with neutrophil and platelet activation. At 1 week, cell cycle arrest and re-entry processes were enriched among mRNA changes, oncogene-induced senescence and MAPK signaling among the proteome changes. Influenza life cycle and infection pathways initiate earlier in mRNA and are reflected among the proteomic changes during the first week. Transcription factor proteins SRC, TGFb and NFATC2 were immediately induced at 1 day after irradiation with increased transcriptional activity as predicted by mRNA changes persisting up to 1 week. Cell counts revealed a mild / moderate hematopoietic acute radiation syndrome (H-ARS) reaction to irradiation with expected lymphopenia, neutropenia and thrombocytopenia that resolved within 30 days. Measurements of micronuclei per binucleated cell levels in cytokinesis-blocked T-lymphocytes remained high in the range 0.27-0.33 up to 28 days and declined to 0.1 by day 56. Conclusions: Overall, we show that the TBI 4 Gy dose in NHPs induces many cellular changes that persist up to 1 month after exposure, consistent with damage, death, and repopulation of blood cells.

Assessment of Micronuclei Frequency in the Peripheral Blood of Adult and Pediatric Patients Receiving Fractionated Total Body Irradiation

“…Based on data from historical accidents, Goans and colleagues [Goans et al, 1997;Goans et al, 2001] reported that the onset of lymphopenia in vivo is rapid and follows an approximate exponential decline within the first 24-48 h following gamma ray exposure. A rapid rise in neutrophil cell counts and decrease in lymphocyte levels in vivo has also been reported in the non-human primate model within 24 h after TBI [Farese et al, 2021;Ghandhi et al, 2023]. Hematology kinetics showed that with increasing time post-exposure, WBCs, neutrophils, lymphocytes, PLTs, and RBCs decreased, highlighting radiation-induced myelosuppression with pancytopenia.…”

Microfluidic measurement of intracellular mRNA with a molecular beacon probe towards point-of-care radiation triage

“…As an alternative method for radiation biodosimetry, additional methods such as γ-H2AX, 6,7 micronuclei, 5,8 microRNA, 9,10 lncRNA, 11,12 and protein [13][14][15] and gene expression signatures [16][17][18] in peripheral blood cells are being developed for this purpose. 19 Gene expression assays have been particularly promising, and typically measure the mRNA content in a certain simulated scenario with reference to normal expression levels.…”