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| Fig. 1: miRNA biogenesis (Source: Wikimedia Commons) |
Acute radiation sickness (ARS) (also known as acute radiation syndrome) is a well-known illness caused by an exposure to a high dose of ionizing radiation in a very short period of time. [1] Ionizing radiation is radiation that has high enough energy to excite electrons away from their atoms or molecules. In the body, this may result double-stranded break in the DNA or single-stranded break in the RNA, resulting in cell death. More often, the ionizing radiation may result in a mutation in the DNA, resulting in ectopic gene expression and/or misregulation of the genome. For instance, ionizing radiation is known to be the definitive and only cause of chronic myelogenous leukemia, which is unregulated cell growth and proliferation of myeloid cells in the bone marrow. [2] Radiation affects people and different organ systems in an additive and dose-dependent manner: [3]
Exposure to radiation that is less than 2 Gy results in mild symptoms
Exposure to radiation that is between 2 and 6 Gy affects the hematologic system and progresses slowly.
Exposure to radiation that is greater than 5 to 6 Gy affects the gastrointestinal system and progresses more rapidly.
Exposure to radiation that is greater than 10 to 20 Gy results in an immediate neurovascular. collapse
Whereas the mechanism by which ionizing radiation under these conditions result in ARS is well studied, finding a right biomarker to predict the level of risk is not; finding the right biomarker is important, because most people exposed to radiation due to accidents are not familiar with what and how much they have been exposed to it. [4] This paper reports one recent study in non-human primates that proposes one such biomarker for effective and efficient triage of affected individuals to estimate the absorbed dose and to predict their risk of developing ARS so that they can be treated appropriately.
miRNAs (microRNAs) are small, non-coding RNAs that have an average length of about 22 nucleotides. miRNAs are differentially expressed in different tissues and organs. For instance, miRNA-451 and miRNA-150 are highly expressed in the bone marrow while miRNA-126 is highly expressed in the lungs. [5,6] Because miRNAs are released from cells via endosomal exocytosis, they circulate in the serum and due to post-transcriptional modifications and accessory proteins, they are highly stable at room temperature, as shown in Fig. 1. These characteristics allow miRNAs to serve as a proxy for the readout for the functionality of different organs; furthermore, because they are circulating in the serum or in the plasma, they are accessible via simple blood draw, making them potentially a useful biomarker to use in triage.
Menon et al. exposed non-human primates with graded doses of whole body irradiation (WBI) and measured miRNA count over the course of seven days. [7] Their data showed a dose-dependent and time-dependent change in the levels and types of circulating miRNA. For instance, miRNA-574-5p increased significantly on day 1, but did not exhibit significant changes when measured on day 3 and day 7. miRNA-150-5p, however, exhibited dose-dependent decrease in abundance over the course of seven days. [7] Furthermore, because these miRNA sequences displayed tissue-specific expression profiles, they could be used to track which tissues were affected and require attention. Because neutrophil count, lymphocyte count and mi-RNA-150-5p abundance show strong correlation, all three can be used to triage a patient and detect the onset of ARS.
While this study may have looked at the number of miRNA and the kind of miRNA to serve as a biomarker for ARS, it is important to note that whether people die from ARS is ultimately dependent on how fast their bone marrow recovers. Bone marrow is the organ where hematopoiesis (blood cell production, including red blood cells and immune cells) occurs in humans. Because it is the site of rapid cell division, it is the site that is more vulnerable to radiation damage in ARS and it is largely responsible for replenishing the depleted cells quickly in the aftermath of radiation. Furthermore, this study was done in non-human primates and the reason why it has been especially difficult to study ARS in humans, especially in the context of genetics, is that many do not survive to give birth.
© Anika Kim. The author warrants that the work is the author's own and that Stanford University provided no input other than typesetting and referencing guidelines. The author grants permission to copy, distribute and display this work in unaltered form, with attribution to the author, for noncommercial purposes only. All other rights, including commercial rights, are reserved to the author.
[1] E. H. Donnelly et al., "Acute Radiation Syndrome: Assessment and Management," South. Med. J. 103, 541 (2010).
[2] S. E. Huether and K. L. McCance, Understanding Pathophysiology, 6th Ed. (Elsevier, 2016), p. 530.
[3] W. F. Blakely et al., "Further Biodosimetry Investigations Using Murine Partial-Body Irradiation Model," Radiat. Prot. Dosim. 159, 46 (2014).
[4] A. L. DiCarlo et al., "Radiation Injury After a Nuclear Detonation: Medical Consequences and the Need for Scarce Resources Allocation," Disaster Med. Public, Suppl. 1, S32 (2011).
[5] N. K. Jacob et al., "Identification of Sensitive Serum MicroRNA Biomarkers for Radiation Biodosimetry," PLoS One 8, e57603 (2013).
[6] N. Ludwig et al., "Distribution of miRNA Expression Across Human Tissues," Nucleic Acids Res. 44, 3865 (2016).
[7] N. Menon et al., "Detection of Acute Radiation Sickness: a Feasibility Study in Non-Human Primates Circulating miRNAs For Triage in Radiological Events," PLoS One 11, e0167333 (2016).
