Detection of Acute Radiation Sickness: A Feasibility Study in Non-Human Primates Circulating miRNAs for Triage in Radiological Events

Abstract

Development of biomarkers capable of estimating absorbed dose is critical for effective triage of affected individuals after radiological events. Levels of cell-free circulating miRNAs in plasma were compared for dose-response analysis in non-human primates (NHP) exposed to lethal (6.5 Gy) and sub-lethal (1 and 3 Gy) doses over a 7 day period. The doses and test time points were selected to mimic triage needs in the event of a mass casualty radiological event. Changes in miRNA abundance in irradiated animals were compared to a non-irradiated cohort and a cohort experiencing acute inflammation response from exposure to lipopolysaccharide (LPS). An amplification-free, hybridization-based direct digital counting method was used for evaluation of changes in microRNAs in plasma from all animals. Consistent with previous murine studies, circulating levels of miR-150-5p exhibited a dose- and time-dependent decrease in plasma. Furthermore, plasma miR-150-5p levels were found to correlate well with lymphocyte and neutrophil depletion kinetics. Additionally, plasma levels of several other evolutionarily and functionally conserved miRNAs were found altered as a function of dose and time. Interestingly, miR-574-5p exhibited a distinct, dose-dependent increase 24 h post irradiation in NHPs with lethal versus sub-lethal exposure before returning to the baseline level by day 3. This particular miRNA response was not detected in previous murine studies but was observed in animals exposed to LPS, indicating distinct molecular and inflammatory responses. Furthermore, an increase in low-abundant miR-126, miR-144, and miR-21 as well as high-abundant miR-1-3p and miR-206 was observed in irradiated animals on day 3 and/or day 7. The data from this study could be used to develop a multi-marker panel with known tissue-specific origin that could be used for developing rapid assays for dose assessment and evaluation of radiation injury on multiple organs. Furthermore this approach may be utilized to screen for tissue toxicity in patients who receive myeloablative and therapeutic radiation.

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

“…Plasma miR-150-5p levels were found to correlate well with lymphocyte and neutrophil depletion kinetics [122]. Also, miR-574-5p exhibited a dose-dependent increase 24 h post irradiation in NHPs with lethal versus sub-lethal exposure and returned to the baseline level by d 3.…”

Extracellular vesicles mediate low dose ionizing radiation-induced immune and inflammatory responses in the blood

“…MiR-150-5p was identified as a circulating miRNA that correlated with delivered dose within a dose range of 1-12 Gy 24-48 h after irradiation. Due to its abundance in lymphocytes, miR-150-5p was proposed as a sensitive marker for lymphocyte depletion and BM damage and a useful bioindicator for radiation biodosimetry (Jacob et al 2013;Menon et al 2016). It was also reported that expression of miR-150-5p in exosomes secreted by non-small cell lung cancer cells and stromal cells decreased with radiation but increased intracellularly both in cancer cells and stromal cells, suggesting that exosomal export of these miRNAs may be downregulated in these cells in response to radiation (Dinh et al 2016;Menon et al 2016).…”

microRNA and Metabolite Signatures Linked to Early Consequences of Lethal Radiation

“…At higher radiation doses in the mouse (~10 Gy and above), damage resulting from radiation exposure can be observed in the GI system in addition to bone marrow, and weight loss; and diarrhea are typically observed, which can lead to dehydration and mortality 6 . There is an increasing traction about determining the role of serum miRNAs in responding to radiation, particularly in the context of biodosimetry 7,8 . A number of reviews highlighted the potential utility of miRNAs as predictors of carcinoma prognosis 9,10 and of drug efficacy 11,12 .…”

“…Cross-species validated radiation marker for time-and dose-dependent reduction in expression in plasma8 . We found subsequent reduction in expressions in the Mid (−1.31) and Late phases (−1.53).…”