Differentiating Total- or Partial-Body Irradiation in Baboons Using mRNA Expression Patterns: A Proof of Concept

Area of Science:

• Radiation Biology
• Genomics
• Biomarker Discovery

Background:

• Accurate assessment of absorbed radiation dose and exposed body areas is crucial for predicting clinical outcomes.
• Previous studies identified microRNAs (miRNAs) as potential biomarkers for total-body irradiation (TBI) and partial-body irradiation (PBI) patterns.
• The potential of messenger RNAs (mRNAs) as biomarkers for radiation exposure patterns requires further investigation.

Purpose of the Study:

• To investigate the utility of whole-genome mRNA expression profiles for predicting radiation exposure patterns (TBI vs. PBI) in a baboon model.
• To identify specific mRNA biomarkers that can discriminate between different radiation exposure scenarios and their timing post-irradiation.
• To compare the temporal dynamics of mRNA expression changes with previously identified miRNA biomarkers.

Main Methods:

• Blood samples were collected from 17 irradiated baboons at multiple time points (pre-irradiation, 1, 2, 7, 28, 75-106 days post-irradiation).
• Baboons received TBI or PBI (upper body, left hemibody) at doses of 2.5 or 5 Gy.
• Whole genome microarrays were used to analyze gene expression; statistical analyses (Kruskal-Wallis, logistic regression, ROC) were employed to identify differentially expressed mRNAs and assess discriminatory power.

Main Results:

• Several hundred significantly deregulated mRNAs (≥2-fold change, P < 0.05) were identified, with a peak at 28 days post-irradiation (163-860 mRNAs).
• A subset of 14 mRNAs (e.g., LTF, DEFA3, OLFM4) showed significant upregulation (10.1-46.2-fold) and high discriminatory power (ROC 0.8-1.0) for exposure patterns.
• mRNA expression changes were associated with the percentage of body exposed, and different biological processes predominated at each time point.

Conclusions:

• mRNA gene expression profiles can be used to retrospectively determine radiation exposure patterns (partial vs. total body) in baboons.
• mRNA biomarkers offer a potential application over a longer time frame (2-75 days) compared to miRNAs, but require dynamic selection based on the time post-irradiation.
• These findings highlight the potential of mRNA expression analysis for biodosimetry and assessing radiation exposure scenarios.