Identification of Sensitive Serum microRNA Biomarkers for Radiation Biodosimetry

Abstract

Exposure to ionizing radiation through environmental, occupational or a nuclear reactor accident such as the recent Fukushima Daiichi incident often results in major consequences to human health. The injury caused by radiation can manifest as acute radiation syndromes within weeks in organs with proliferating cells such as hematopoietic and gastrointestinal systems. Cancers, fibrosis and degenerative diseases are also reported in organs with differentiated cells, months or years later. Studies conducted on atom bomb survivors, nuclear reactor workers and animal models have shown a direct correlation of these effects with the absorbed dose. Physical dosimeters and the available radio-responsive biologics in body fluids, whose responses are rather indirect, have limitations to accurately evaluate the extent of post exposure damage. We have used an amplification-free, hybridization based quantitative assay utilizing the nCounter multiplex platform developed by nanoString Technologies to compare the levels of over 600 miRNAs in serum from mice irradiated at a range of 1 to 12 Gy at 24 and 48 hr time points. Development of a novel normalization strategy using multiple spike-in oligonucleotides allowed accurate measurement of radiation dose and time dependent changes in serum miRNAs. The response of several evolutionarily conserved miRNAs abundant in serum, were found to be robust and sensitive in the dose range relevant for medical triage and in patients who receive total body radiation as preparative regimen for bone marrow transplantation. Notably, miRNA-150, abundant in lymphocytes, exhibited a dose and time dependent decrease in serum, which we propose as a sensitive marker indicative of lymphocyte depletion and bone marrow damage. Our study has identified several markers useful for evaluation of an individual’s response by minimally invasive methods, relevant to triage in case of a radiation accident and evaluation of toxicity and response during and after therapeutic radiation.

Time, Dose and Ataxia Telangiectasia Mutated (ATM) Status Dependency of Coding and Noncoding RNA Expression after Ionizing Radiation Exposure

“…It is very likely that after in vivo irradiation, the blood will contain other radiation-responsive miRNAs in exosomes. For example, Jacob et al (25) identified miR-150 as a sensitive biomarker of in vivo exposure in mouse serum.…”

“…This published finding inspired the search for other radiation-responsive miRNAs (19)(20)(21)(22). The radiation-induced miRNA response depends on radiation dose, time post exposure, genetic background (23)(24)(25)(26), the tissue being investigated and gender (27)(28)(29).…”

Extracellular miR-1246 promotes lung cancer cell proliferation and enhances radioresistance by directly targeting DR5

“…The extracellular miRNAs that can function in recipient cells are named as shuttle miRNAs, it may convey specific information from its donor cells to other recipient cells and hence plays various physiological functions. Recent studies have suggested that the expressions of specific miRNAs in blood plasma could be used as biomarkers of radiation dosimetry [17, 18]. …”

Nuclear Abnormalities of Lymphocytes as the Simplest Markers for Bioindication Test in Case of Mass Casualty Events Involving Radiation Exposure

“…Frequency of occurrence of cells with dumbbell-shaped nuclei depends on the dose of irradiation and this correlation is described by a linearquadratic function with the following equation: y = 0.003+0.014x +0.005x 2 [31]. We would like to emphasize that the simplest biomarkers (nuclei abnormalities) we suggest for radiation exposure detection in vivo is not an alternative to classical radiation biomarkers in vitro [17], as well as to other modern approaches [2][3][4][5][44][45][46]. Detection of chromosomal aberrations (dicentrics) and the cytochalasine B micronucleus and "Cytome" methods are reliable bioindication and biodosimetry methods.…”