Serum microRNA Analysis of Nonhuman Primates Prophylaxed with Gamma-tocotrienol and Exposed to Total- or Partial-body Radiation

Abstract

Ionizing radiation exposure is a rising military and national security risk. Exposure to a high dose can lead to an illness called acute radiation syndrome (ARS), which poses clinical challenges. There is no Food and Drug Administration (FDA)-approved agent that can be used prior to radiation exposure for prophylaxis against ARS. Gamma-tocotrienol (GT3), a member of the vitamin E family, has demonstrated efficacy as a radiation medical countermeasure (MCM) when administered prophylactically in nonhuman primates (NHPs). Serum microRNA (miRNA) profiles have been shown to be effective radiation biomarkers and are useful for translating drug doses from NHPs to humans. In this study, 32 rhesus macaques ( Macaca mulatta ) were administered GT3, then exposed to 12 Gy of either total- or partial-body irradiation (TBI or PBI). Serum samples were collected prior to irradiation and at seven time points postirradiation: –3 days, 4 h, 8 h, 12 h, day 1, day 2, and pre-final. This integrated NHP study shows that radiation exposure geometry and dose context appear to shape circulating miRNA signatures, tissue injury patterns, and the likelihood of therapeutic benefit. TBI induced massive, muscle-specific miRNA surges (e.g., miR-133 up to 450-fold), potentially enabling early biodosimetry of necrotic injury but exceeding the therapeutic window, as GT3 produced clear molecular engagement (292 modulated miRNAs with oxidative/immune pathway enrichment) without survival benefit. PBI generated a distinct miRNA pattern (386 unique miRNAs) highlighting growth hormone axis disruption suggesting targeted interventions remain viable. Together, these findings suggest that circulating miRNAs can report radiation dose patterns and distinguish molecular engagement from true protection. But this emphasizes the need for model-specific, context-aware biomarker and intervention strategies.