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

PLoS One. 2018 Jan 19;13(1):e0191402. doi: 10.1371/journal.pone.0191402. eCollection 2018.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Cell Count
  • Blood Cells / metabolism*
  • Blood Cells / radiation effects*
  • Chromosome Aberrations
  • DNA Damage*
  • Dose-Response Relationship, Radiation
  • Gene Expression / radiation effects*
  • Gene Ontology
  • Humans
  • Lung Injury / blood
  • Lung Injury / etiology
  • Lung Injury / genetics
  • Macaca mulatta / blood
  • Macaca mulatta / genetics
  • Male
  • Micronucleus Tests
  • Radiation Injuries, Experimental / blood
  • Radiation Injuries, Experimental / genetics
  • Thorax / radiation effects
  • Time Factors