Metabolomic applications in radiation biodosimetry: exploring radiation effects through small molecules

Abstract

Purpose: Exposure of the general population to ionizing radiation has increased in the past decades, primarily due to long distance travel and medical procedures. On the other hand, accidental exposures, nuclear accidents, and elevated threats of terrorism with the potential detonation of a radiological dispersal device or improvised nuclear device in a major city, all have led to increased needs for rapid biodosimetry and assessment of exposure to different radiation qualities and scenarios. Metabolomics, the qualitative and quantitative assessment of small molecules in a given biological specimen, has emerged as a promising technology to allow for rapid determination of an individual's exposure level and metabolic phenotype. Advancements in mass spectrometry techniques have led to untargeted (discovery phase, global assessment) and targeted (quantitative phase) methods not only to identify biomarkers of radiation exposure, but also to assess general perturbations of metabolism with potential long-term consequences, such as cancer, cardiovascular, and pulmonary disease.

Conclusions: Metabolomics of radiation exposure has provided a highly informative snapshot of metabolic dysregulation. Biomarkers in easily accessible biofluids and biospecimens (urine, blood, saliva, sebum, fecal material) from mouse, rat, and minipig models, to non-human primates and humans have provided the basis for determination of a radiation signature to assess the need for medical intervention. Here we provide a comprehensive description of the current status of radiation metabolomic studies for the purpose of rapid high-throughput radiation biodosimetry in easily accessible biofluids and discuss future directions of radiation metabolomics research.

Keywords: Ionizing radiation; biofluids; lipidomics; metabolomics; radiation signatures; rapid biodosimetry.

Figure 1

Acute radiation syndrome (ARS) in the human population is primarily divided in 4 different categories. Below 2 Gy, some individuals may experience some symptoms, such as emesis, however these individuals will not require immediate medical intervention for survival. Over doses of 2 Gy, individuals will experience and expire from myelosuppression (hematopoietic syndrome). The LD_50/60 without medical intervention is ∼3.5 Gy, however with medical intervention it shifts upwards to ∼7 Gy. Only two medications have been FDA approved for the hematopoietic syndrome, Neupogen^® and Neulasta^®. Individuals exposed with a dose of 10 Gy and above will expire from gastrointestinal (GI) syndrome within 7-14 days post irradiation, although some individuals can have symptoms of GI syndrome with as low as 6 Gy. Individuals exposed to doses >20 Gy, although some can show symptoms as low as 10 Gy, will expire within days from cardiovascular and/or central nervous system syndromes. Since not all individuals can undergo an invasive procedure such as hematopoietic stem cell transplantation, only a small percentage falling between a dose range that cannot adequately benefit from cytokine therapy and antibiotic treatments, will be candidates for such treatments. Sources for the information include (DiCarlo et al., 2011, Sullivan et al., 2013, CDC, 2015).

Figure 2

A simplified illustration of the metabolomic processes, untargeted (global profiling) and targeted approaches. LC-MS, GC-MS, and ¹H-NMR have all been used successfully to identify biomarkers of radiation exposure. Targeted approaches, primarily through LC-MS, have provided quantitative information on select metabolites and could be utilized for high-throughput analysis of samples in a real life scenario to accurately identify individuals who have been exposed to ionizing radiation.