Abstract
We investigated the cytogenetic and gene expression responses of peripheral blood cells of non-human primates (NHP, Macaca mulatta) that were whole-thorax irradiated with a single dose of 10 Gy. In this model, partial irradiation of NHPs in the thoracic region (Whole Thorax Lung Irradiation, WTLI) allows the study of late radiation-induced lung injury, while avoiding acute radiation syndromes related to hematopoietic and gastrointestinal injury. A transient drop in circulating lymphocytes and platelets was seen by 9 days, followed by elevations in respiratory rate, circulating neutrophils, lymphocytes, and monocytes at 60–100 days, corresponding to computed tomography (CT) and histologic evidence of pneumonitis, and elective euthanasia of four animals. To evaluate long-term DNA damage in NHP peripheral blood lymphocytes after 10 Gy WTLI, we used the cytokinesis-block micronucleus (CBMN) assay to measure chromosomal aberrations as post-mitotic micronuclei in blood samples collected up to 8 months after irradiation. Regression analysis showed significant induction of micronuclei in NHP blood cells that persisted with a gradual decline over the 8-month study period, suggesting long-term DNA damage in blood lymphocytes after WTLI.We also report transcriptomic changes in blood up to 30 days after WTLI. We isolated total RNA from peripheral blood at 3 days before and then at 2, 5 and 30 days after irradiation. We identified 1187 transcripts that were significantly changed across the 30-day time course. From changes in gene expression, we identified biological processes related to immune responses, which persisted across the 30-day study. Response to oxygen-containing compounds and bacteria were implicated by gene-expression changes at the earliest day 2 and latest, day 30 time-points. Gene expression changes suggest a persistent altered state of the immune system, specifically response to infection, for at least a month after WTLI.
Highlights
The Non-Human Primate (NHP) is the most appropriate model for the study of radiation response and injury, as well as for assessing the effect of mitigators of acute radiation syndrome (ARS) and lung Delayed Effects of Acute Radiation Exposure (DEARE) [1]
Our study focused on Whole Thorax Lung Irradiation (WTLI) of NHP and long-term changes in peripheral blood at the cytogenetic and transcriptomic levels; and was part of a larger study of a novel mitigator of lung injury
NHP have been used in radiation dose response studies for many decades [9,10,11, 17, 46], focusing on the effects of mitigators on acute radiation syndromes of different organ systems and mortality
Summary
The Non-Human Primate (NHP) is the most appropriate model for the study of radiation response and injury, as well as for assessing the effect of mitigators of acute radiation syndrome (ARS) and lung Delayed Effects of Acute Radiation Exposure (DEARE) [1]. NHPs mimic humans in many ways including similarities in genome, neuroanatomy, neurophysiology, immunogenetics, and age-related changes in immune function [3, 4]. NHPs share similar hematopoietic stem cell dynamics, engraftment properties, and cytokine requirements with humans [5, 6]. Positive selection of genes in the human genome appear to be enriched in biological functions related to immune response and signal transduction [7], making M. mulatta a relevant NHP model for molecular studies and cytogenetic analyses [8]
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