Serum Metabolomic Alterations Associated with Cesium-137 Internal Emitter Delivered in Various Dose Rates

Abstract

Our laboratory and others have use radiation metabolomics to assess responses in order to develop biomarkers reflecting exposure and level of injury. To expand the types of exposure and compare to previously published results, metabolomic analysis has been carried out using serum samples from mice exposed to 137Cs internal emitters. Animals were injected intraperitoneally with 137CsCl solutions of varying radioactivity, and the absorbed doses were calculated. To determine the dose rate effect, serum samples were collected at 2, 3, 5, 7, and 14 days after injection. Based on the time for each group receiving the cumulative dose of 4 Gy, the dose rate for each group was determined. The dose rates analyzed were 0.16 Gy/day (low), 0.69 Gy/day (medium), and 1.25 Gy/day (high). The results indicated that at a cumulative dose of 4 Gy, the low dose rate group had the least number of statistically significantly differential spectral features. Some identified metabolites showed common changes for different dose rates. For example, significantly altered levels of oleamide and sphingosine 1-phosphate were seen in all three groups. On the other hand, the intensity of three amino acids, Isoleucine, Phenylalanine and Arginine, significantly decreased only in the medium dose rate group. These findings have the potential to be used in assessing the exposure and the biological effects of internal emitters.

Irradiation Causes Alterations of Polyamine, Purine, and Sulfur Metabolism in Red Blood Cells and Multiple Organs

“…Similar alterations to the microbiome (especially, members of the bacterial taxa Lachnospiraceae and Enterococcaceae) and metabolites of potential microbial origin (including tryptophan-derived indoles) have been reported in the plasma of humans surviving ionizing radiation exposure. , Studies have also confirmed alterations in tryptophan/indole metabolism in low-dose uranium radiation exposure studies . Studies on serum and plasma have been reported at a low dose of radiation (e.g., 4 Gy) or urine (with a total dose of radiation between 5 and 10 Gy over a 30 day period) . Metabolomic studies examining the impact of bone marrow failure-inducing doses of radiation have also been published to document the effect on mice exposed to a higher radiation dose range (5–11 Gy).…”

“…Metabolomic studies examining the impact of bone marrow failure-inducing doses of radiation have also been published to document the effect on mice exposed to a higher radiation dose range (5–11 Gy). These identified a significant enrichment in purine metabolism, tricarboxylic acid cycle, fatty acids, acyl-carnitines, and amino acids in the spleen of animals upon early perturbations with γ irradiation . Despite several studies focusing on plasma, to the best of our knowledge, dose–response studies focusing on plasma, blood, and multiple organs have not been published yet, making it difficult to appreciate system-wide responses to radiation.…”

Biofluid Metabolomics of Mice Exposed to External Low-Dose Rate Radiation in a Novel Irradiation System, the Variable Dose-Rate External 137Cs Irradiator

“…While the above studies demonstrated several biophysiological consequences of LDR IR exposure, they used a static dose rate that does not replicate the biokinetics of internally deposited 137 Cs associated with nuclear fallout. To address the variable dose rate encountered in a realistic exposure scenario from internal deposition, our group previously designed a set of experiments that used 137 CsCl (aq) and 90 SrCl 2(aq) injections in mice and demonstrated several downstream perturbations at the transcriptomic − and metabolomic levels. − However, inherent challenges associated with this design, such as the need for specialized facilities and instrument contamination from radioactive biofluids, limits the use of its application and does not effectively model external fallout exposures.…”

Biofluid Metabolomics and Lipidomics of Mice Exposed to External Very High-Dose Rate Radiation

“…Ideally, the top candidates from both of these disciplines can be combined into a single rapid multiplex assay useful in dose reconstruction and be effective irrespective of the complex nature associated with radiation exposures (e.g., dose rate), combined injury, genetic predisposition, etc. A particular recent focus of our group has been elucidating the effects of dose-rate on biofluid signatures and its potential to alter predictive model power [5][6][7][8][9].…”

“…Third, internal emitter radiation, of primary concern the radioisotope 137 Cs, can continue for weeks if chelating agents are not used [11]. As our previous research addressed effects of internal emitters or nuclear fallout on dose reconstruction [5,[7][8][9]12], further research is also needed in the VHDR range.…”