Long-term Radiation Signal Persistence in Urine and Blood: A Two-year Analysis in Non-human Primates Exposed to a 4 Gy Total-Body Gamma-Radiation Dose.

National security concerns regarding radiological incidents, accidental or intentional in nature, have increased substantially over the past few years. A primary area of intense planning is the assessment of exposed individuals and timely medical management. However, exposed individuals who receive survivable radiation doses may develop delayed effects of acute radiation exposure many months or years later. Therefore, it is necessary to identify such individuals and determine whether their symptoms may have been initiated by radiation and require complex medical interventions. We previously developed early response metabolomic biosignatures in biofluids from non-human primates exposed to a total body gamma radiation dose of 4 Gy (up to 60 days). A follow-up of these animals has been ongoing with samples consistently collected every few months for up to 2 years after exposure, providing a unique cohort to determine if a radiation signal persists longer than 2 months. Metabolic fingerprinting in urine and serum determined that exposed animals remain metabolically different from pre-exposure levels and from age-matched controls, and the pre-determined biosignature maintains high sensitivity and specificity. Significant perturbations in tricarboxylic acid intermediates, cofactors and nucleotide metabolism were noted, signifying energetic changes that could be attributed to or perpetuate altered mitochondrial dynamics. Importantly, these animals have begun developing diseases such as hypertension much earlier than their age-matched controls, further emphasizing that radiation exposure may lead to accelerated aging. This NHP cohort provides important information and highlights the potential of metabolomics in determining persistent changes and a radiation-specific signature that can be correlated to phenotype.