Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection

Abstract

Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In order to identity such candidate biomarkers of radiation exposure, high-resolution proteomics was used to analyze plasma from non-human primates following whole body irradiation (Co-60 at 6.7 Gy and 7.4 Gy) with a twelve day observation period. A total of 663 proteins were evaluated from the plasma proteome analysis. A panel of plasma proteins with characteristic time- and dose-dependent changes was identified. In addition to the plasma proteomics study reported here, we recently identified candidate biomarkers using urine from these same non-human primates. From the proteomic analysis of both plasma and urine, we identified ten overlapping proteins that significantly differentiate both time and dose variables. These shared plasma and urine proteins represent optimal candidate biomarkers of radiation exposure.

Nonhuman primates as models for the discovery and development of radiation countermeasures

“…In the recent past, radiation biologists have redirected their efforts to investigate chemical alternatives in biological fluid metabolome, biological alternatives in the gut microbiome, and other molecules of interest. There are several studies identifying proteins [129,130], metabolites as biomarkers for radiation exposure in blood [131–133], urine [131,134,135], and the gut using NHP models [135–139]. In addition, there are ample studies with lipidomics [132], microbiome [140], and mRNA [141].…”

Candidate protein markers for radiation biodosimetry in the hematopoietically humanized mouse model

“…Applications of proteome profiling in radiation research are increasing, particularly as the research aims to study not only protein expression, but also function, structure, modifications and interactions 24 . Recently, proteomic changes in plasma and urine after irradiation of NHPs have also been studied 14 , 15 . In this study, we used global proteomics analysis to identify novel radiation biomarkers in X-irradiated human lymphocytes isolated from the Hu-NSG mouse spleen.…”

“…Using the NHP model, C-reactive protein (CRP), SAA, IL-6, Flt3L protein biomarkers expressed in NHP plasma have been proposed as early indicators of dose assessment and radiation-induced injury up to ~7 days post irradiation 12 , 13 . Recently, proteomics-based technology has been used to discover novel biomarkers for radiation biodosimetry in NHP models 14 , 15 .…”

Time‐Dependent Measurement of Nrf2‐Regulated Antioxidant Response to Ionizing Radiation Toward Identifying Potential Protein Biomarkers for Acute Radiation Injury

“…In recent years, applications of proteomics in radiation research have increased with advancement in high‐throughput MS technologies. Several groups have developed or implemented state‐of‐the‐art quantitative proteomics tools to identify and validate protein biomarker signatures associated with radiation exposure . Our focus has been on the master regulator of anti‐oxidant responses, NF‐E2‐Related Factor 2 (Nrf2).…”