Pseudo Pelger-Huët anomalies as potential biomarkers for acute exposure radiation dose in rhesus macaques (Macaca mulatta)

Abstract

Purpose

The potential for malicious use of radiation, or radiation accidents could potentially lead to acute, high radiation doses to the public. Following acute accidental exposure to high doses of radiation, medical intervention is pivotal to the survivability of the patient, and the sooner the appropriate measures are taken the better the odds for survival. Early estimates of acute accidental radiation doses can be determined via biomarkers such as dicentric chromosome analysis or scenario reconstruction using computer software. However, both take valuable time and can be expensive. Increased frequencies of abnormal neutrophils in peripheral blood, referred to as pseudo Pelger-Huët anomalies (PPHAs), have been shown to be potential biomarkers of radiation exposure in several scenarios, including the 1958 Y-12 criticality accident and the radium dial painters. PPHAs are potentially a faster and cheaper quantitative biomarker for radiation exposure, and here they were evaluated in acutely exposed rhesus macaques.

Methods and materials

Peripheral blood smears from acutely exposed rhesus macaques were evaluated for the percentage of neutrophils that displayed the PPHA morphology using light microscopy. Irradiated animals received 0 to 8.5 Gy total body radiation using one of two strategies: (1) linear accelerator-produced 6 MV photons delivered at 80 cGy/minute; or (2) Cobalt 60-produced gamma irradiation delivered at 60 cGy/min. Zero dose animals were used to determine a baseline percentage of PPHAs, and blood smears taken periodically throughout the lifetime of exposed animals post-irradiation were used to determine the persistence and biokinetics of PPHAs.

Results

The baseline prevalence of the PPHA in rhesus macaques was determined to be 0.58 ± 0.46%. The dose-response curve with doses ranging from 0 Gy to 8.5 Gy (LD90/30) displayed a strong positive correlation between PPHA percentage and acute radiation dose (R² of 0.88 p =  3.62 × 10⁻²²). Statistically significant differences were found when animals were separated into dose cohorts of 0, 4, 6.4–6.5, and 8–8.5 Gy. The biokinetics model utilized only 4 Gy exposures and blood smears taken periodically over 3.1 years post-irradiation. PPHA morphology increases quickly following irradiation and appears stable over 3.1 years post-irradiation.

Conclusion

PPHA morphology was confirmed to be present in rhesus macaques, a dose-response relationship was constructed, and it is stable over 3 years post-irradiation. This study demonstrates that PPHA analysis can be a fast and cheap method of biodosimetry. Future studies will work to determine the accuracy of dose determination and lower limits of detection.

Keywords:

• Biodosimetry
• biomarkers
• pseudo Pelger-Huët anomaly
• rhesus macaque
• dose-response curve

Disclosure statement

The authors declare no actual or potential conflict of interest including any financial, personal, or other relationships with other persons or organizations that could inappropriately influence their work. The authors alone are responsible for the content and writing of this paper.

Additional information

Funding

This work was supported by the grant T42OH009229, funded by the National Institute of Occupational Safety and Health in the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. This work was additionally supported in part by NIH U01AI150578 (JM Cline, PI), NIH U19A167798 (N Chao, PI) and DOD CDMRP W81XWH-15-1-0574 (JM Cline, PI).

Notes on contributors

Joshua M. Hayes

Joshua M. Hayes, Ph.D., is an Associate Radiobiologist/Biodosimetrist at the Biological Dosimetry Model Laboratory, in the section of Applied Radiobiology and Radiotherapy, Division of Human Health, Department of Nuclear Sciences and Applications, International Atomic Energy Agency, Vienna, Austria.

John D. Olson

John D. Olson, MS, MS, is a Research Associate and Resource Manager for the NHP Radiation Late Effects Cohort at the Department of Pathology Section on Comparative Medicine, School of Medicine, Wake Forest University, Winston-Salem, NC, USA.

Yuiko Chino

Yuiko Chino, MS, is a Ph.D. Candidate in the Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado, USA, 80523-1618.

J. Daniel Bourland

J. Daniel Bourland, Ph.D., is Professor, Departments of Radiation Oncology, Physics, and Biomedical Engineering a Department of Radiation Oncology Wake Forest School of Medicine, Wake Forest University, Winston-Salem, NC, USA.

J. Mark Cline

J. Mark Cline, DVM, Ph.D., DACVP, is a Professor of Pathology/Comparative Medicine and Radiation Oncology at Wake Forest School of Medicine, Winston-Salem, NC, USA.

Thomas E. Johnson

Thomas E. Johnson, Ph.D., is a Professor in the Department of Environmental and Radiological Health Sciences Colorado State University, Fort Collins, CO, USA.