Metabolomic Studies of Tissue Injury in Nonhuman Primates Exposed to Gamma-Radiation

Abstract

Exposure to ionizing radiation induces a complex cascade of systemic and tissue-specific responses that lead to functional impairment over time in the surviving population. However, due to the lack of predictive biomarkers of tissue injury, current methods for the management of survivors of radiation exposure episodes involve monitoring of individuals over time for the development of adverse clinical symptoms and death. Herein, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that were exposed to a single dose of 7.2 Gy whole-body 60Co γ-radiation that either survived or succumbed to radiation toxicities over a 60-day period. This study involved the delineation of the radiation effects in the liver, kidney, jejunum, heart, lung, and spleen. We found robust metabolic changes in the kidney and liver and modest changes in other tissue types at the 60-day time point in a cohort of NHPs. Remarkably, we found significant elevation of long-chain acylcarnitines in animals that were exposed to radiation across multiple tissue types underscoring the role of this class of metabolites as a generic indicator of radiation-induced normal tissue injury. These studies underscore the utility of a metabolomics approach for delineating anticipatory biomarkers of exposure to ionizing radiation.

Plasma metabolomic profiles in liver cancer patients following stereotactic body radiotherapy

“…Following only one to two fractions of SBRT, higher plasma levels of the glycerophospholipids such as PC aa C30:0 and PC ae C30:0 were detected in the HCC patients with higher baseline CP score and ALBI grade compared to their lower score/grade counterparts, suggesting increased radiation-induced lipid turnover in the impaired livers. In line with our findings, some preclinical studies previously demonstrated significant dysregulation of various glycerophospholipids in the liver of non-human primates and rats at early (3 days) and late (60 days) time points following a single dose of whole body irradiation (which included the whole liver) compared to that of healthy controls who did not receive whole body irradiation [ 22 , 23 ]. Dysregulation of glycerophospholipids has also been reported in prostate cancer patients who developed urinary symptoms following prostate SBRT [24] .…”

Proteomic Evaluation of the Natural History of the Acute Radiation Syndrome of the Gastrointestinal Tract in a Non-human Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing Includes Dysregulation of the Retinoid Pathway

“…Proteomic profiling reports have included mouse and intestinal epithelial cell models (Bo et al 2005;Lim et al 2011;Huang et al 2019). More studies have focused on the complementary metabolome; metabolomic interrogation of intestine after radiation exposure has been reported for mouse, rat and NHP (Cheema et al 2014;Jang et al 2016;Cheema et al 2019a;Cheema et al 2019b;Jones et al 2019) and Kumar, Wang, et al in this issue. Additionally, a mass spectrometry imaging interrogation of the lipid alterations across the natural history of the PBI/BM2.5 model has been reported (Carter et al 2019).…”

Effects of Low Dose Space Radiation Exposures on the Splenic Metabolome

“…Given this, the spleen is an important organ in fighting infections from bacteria and viruses [ 27 ], and, therefore, perturbations by exogenous genotoxic factors, such as ionizing radiation (IR), may lead to organ dysfunction. Data from low dose rate exposures [ 28 ] or high dose acute exposures [ 29 , 30 , 31 ] have shown significant effects on the spleen, including altered metabolism.…”