Abstract
Tissue consequences of radiation exposure are dependent on radiation quality and high linear energy transfer (high-LET) radiation, such as heavy ions in space is known to deposit higher energy in tissues and cause greater damage than low-LET γ radiation. While radiation exposure has been linked to intestinal pathologies, there are very few studies on long-term effects of radiation, fewer involved a therapeutically relevant γ radiation dose, and none explored persistent tissue metabolomic alterations after heavy ion space radiation exposure. Using a metabolomics approach, we report long-term metabolomic markers of radiation injury and perturbation of signaling pathways linked to metabolic alterations in mice after heavy ion or γ radiation exposure. Intestinal tissues (C57BL/6J, female, 6 to 8 wks) were analyzed using ultra performance liquid chromatography coupled with electrospray quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) two months after 2 Gy γ radiation and results were compared to an equitoxic 56Fe (1.6 Gy) radiation dose. The biological relevance of the metabolites was determined using Ingenuity Pathway Analysis, immunoblots, and immunohistochemistry. Metabolic profile analysis showed radiation-type-dependent spatial separation of the groups. Decreased adenine and guanosine and increased inosine and uridine suggested perturbed nucleotide metabolism. While both the radiation types affected amino acid metabolism, the 56Fe radiation preferentially altered dipeptide metabolism. Furthermore, 56Fe radiation caused upregulation of ‘prostanoid biosynthesis’ and ‘eicosanoid signaling’, which are interlinked events related to cellular inflammation and have implications for nutrient absorption and inflammatory bowel disease during space missions and after radiotherapy. In conclusion, our data showed for the first time that metabolomics can not only be used to distinguish between heavy ion and γ radiation exposures, but also as a radiation-risk assessment tool for intestinal pathologies through identification of biomarkers persisting long after exposure.
Highlights
Space travel beyond low earth orbit exposes astronauts to radiation from solar particle events (SPE), galactic cosmic radiation (GCR), and earth’s magnetosphere (Van Allen belt) [1]
C radiation exposure led to significant perturbation of 1222 features and 56Fe radiation resulted in perturbation of 346 features (Table 1)
Exposure to ionizing radiation (IR) at non-lethal doses initiates a cascade of complex cellular response, which others and we have reported to be a continuous process [11,58,59,60,61]
Summary
Space travel beyond low earth orbit exposes astronauts to radiation from solar particle events (SPE), galactic cosmic radiation (GCR), and earth’s magnetosphere (Van Allen belt) [1]. Current uncertainties in the assessment of risk to gastrointestinal (GI) tissues restrain the permissible duration of astronauts’ stay in space. Both small and large intestine are involved in the absorption of essential nutrients and radiation exposure has been reported to perturb intestinal cell physiology to affect nutrient absorption and human health [8,9,10]. Heavy ion radiation due to its higher relative biological effectiveness (RBE) compared to c and proton radiation [12,13] is expected to have greater potential to adversely affect intestinal cell metabolic activities and raising human health concern during prolong space travel
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