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.
Highlights
The lack of reliable biomarkers for evaluation of the extent of damage by radiation injury presents an impediment to medical decision-making regarding the triage and treatment of persons who might be at risk for developing Acute Radiation Sickness (ARS) following a nuclear/radiological accident or attack [1]
We present the hematological parameters and circulating miRNA responses in non-human primates (NHP) exposed to total body irradiation at a low (1 Gy), sub-lethal (3 Gy) and a potentially lethal dose (6.5 Gy), evaluated at days 1, 3 and 7, the time points most relevant to triage in a radiological events [5,28,29]
Neutrophil counts were less sensitive to whole body irradiation (WBI), with significant decreases apparent only after day 4 and only for doses ! 3 Gy (p-value < 0.005; Fig 1B)
Summary
The lack of reliable biomarkers for evaluation of the extent of damage by radiation injury presents an impediment to medical decision-making regarding the triage and treatment of persons who might be at risk for developing Acute Radiation Sickness (ARS) following a nuclear/radiological accident or attack [1]. ARS in humans follows a deterministic path whereby dose effects have distinct clinical outcomes: generally less than 2 Gy exhibit mild symptoms and hematological effects are prominent at doses between 2 and 6 Gy and progress slowly. Hematological system being the most sensitive, lymphocytic depletion kinetics and evaluation of neutrophil counts, together with clinical symptoms, are commonly used to determine radiation exposure levels [6,7,8]. Dose estimation based on hematological parameters requires multiple reading over days [9]. Dose estimation based on hematological parameters hold value only when exposure happens to the whole body or with significant coverage to the bone marrow. Inability to determine organ specific damage and fluctuations due to common differences in genetic and immune responses affect the readout, especially during partial body exposure to ionizing radiation. There is an urgent need for identifying robust biomarkers that allow estimation of the absorbed dose and provide readout of physiological response of various organs
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