Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells

• Published in: PloS one Vol. 13; no. 1; p. e0191402
• Main Authors: Ghandhi, Shanaz A, Turner, Helen C, Shuryak, Igor, Dugan, Gregory O, Bourland, J Daniel, Olson, John D, Tooze, Janet A, Morton, Shad R, Batinic-Haberle, Ines, Cline, J Mark, Amundson, Sally A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.01.2018; Public Library of Science (PLoS)
• Subjects: Animals; Biological activity; Biology and Life Sciences; Blood; Blood Cell Count; Blood cells; Blood Cells - metabolism; Blood Cells - radiation effects; Bone marrow; Causes of; Chromosome Aberrations; Computed tomography; Cytogenetics; Cytokinesis; Deoxyribonucleic acid; DNA; DNA Damage; Dose-Response Relationship, Radiation; Euthanasia; Gene expression; Gene Expression - radiation effects; Gene Ontology; Genetic aspects; Genomes; Humans; Immune response; Immune system; Injury prevention; Ionizing radiation; Irradiation; Leukocytes (neutrophilic); Lung diseases; Lung Injury - blood; Lung Injury - etiology; Lung Injury - genetics; Lungs; Lymphocytes; Macaca mulatta - blood; Macaca mulatta - genetics; Male; Medicine and Health Sciences; Micronuclei; Micronucleus Tests; Monocytes; Neutropenia; Oxygen; Peripheral blood; Physiological aspects; Platelets; Pneumonitis; Primates; Radiation; Radiation damage; Radiation effects; Radiation injuries; Radiation Injuries, Experimental - blood; Radiation Injuries, Experimental - genetics; Regression analysis; Respiration; Respiratory rate; Ribonucleic acid; RNA; Signal transduction; Studies; Thorax; Thorax - radiation effects; Time Factors; Transcriptomics; United States; North Carolina; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0191402

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.