Wollschlaeger, D. | Search bioRxiv

bioRxiv2026

Comparative Transcriptional Responses of Human Blood to Neutron and Photon Irradiation

Despite the well-known health risks of neutron exposures, key gaps remain in understanding neutron-induced molecular responses and identifying reliable biodosimetric markers that distinguish neutrons from photon exposure. We provide the first genome-wide analysis of the human blood transcriptional response to an accelerator-derived fission-like spectrum of neutrons versus photons, evaluating transcriptomic relative biological effectiveness (RBE) and radiation quality-discriminating gene signatures. Whole blood from healthy donors was irradiated ex vivo with X-rays (140 kV, 0-4 Gy, n = 3) or neutrons (0.1-8 MeV, 0-1 Gy, n = 2), incubated for 6 h or 24 h, and processed for RNA sequencing from peripheral blood mononuclear cells (PBMCs). Neutrons were markedly more potent than X-rays at inducing differentially expressed genes (DEGs) at equal doses, showing a peak response 6 h post-irradiation followed by a decline. In contrast, X-rays caused a continuous increase in DEGs up to 24 h (neutrons vs. X-rays at 1 Gy: 1,449 vs. 121 DEGs at 6 h; 996 vs. 621 DEGs at 24 h). A universal p53-centered 34-gene signature, including FDXR, EDA2R, GADD45A, and ZMAT3, showed highly monotonic dose responses (Spearman correlation coefficient {approx} 1) across donors, radiation qualities, and timepoints. Additionally, difference-in-differences analysis identified radiation quality-discriminating genes only at 6 h, with transcriptional convergence observed by 24 h, suggesting a very narrow time window for biodosimetric differentiation. We identified a neutron-specific gene signature driven by cGAS-STING-NF-{kappa}B signaling (RELB, NFKB1, C3, MALAT1) and suppression of B-cell and myeloid identity genes (IGHD, TCL1A, CLEC7A, TLR2), defining a biologically coherent neutron quality index with distinct immunomodulatory effects. For the first time, we assessed neutron RBEs at the gene, pathway, and global transcriptomic levels in a human blood model, reporting a global transcriptomic neutron RBE of 1.30 (95% CI: 1.14-1.49) at 6 h and 1.21 (95% CI: 1.14-1.28) at 24 h, providing a valuable basis for biodosimetry in mixed-field exposure scenarios. Our findings advance the mechanistic understanding of neutron radiation responses and support the development of biodosimetric approaches for mixed-field exposure scenarios.

biophysics↗

bioRxiv2025

Genome-wide transcriptomic response of whole blood to radiation

The hematological system is impacted in nearly all ionizing radiation exposure scenarios. Whole transcriptome data offer detailed insights into bloods radiation response, crucial for radiotherapy and biodosimetry. We conducted genome-wide RNA-seq analysis on blood from three donors irradiated ex vivo with X-rays and incubated for 2h and 6h. Gene expression was subject to strong inter-donor variation and time post-exposure. After 0.5, 1, 2, and 4 Gy X-rays, 5, 33, 84, and 364 genes (2h) and 72, 99, 274, and 607 genes (6h) were differentially expressed (DEG), compared to 0 Gy. The corresponding number of the inferred transcription factors was 255, 253, 274, and 292 after 2h and 214, 245, 262, and 279 after 6h. In sham-irradiated blood, 924 DEGs and 165 transcription factors were affected by ex vivo incubation alone. We identified 34 radioresponsive DEGs not previously described, 8 and 9 showing significant positive or negative correlations with dose, respectively, including GPN1, MRM2, G0S2, and PTPRS. DNA damage signaling pathways were affected from the lowest dose, with doses [≥] 2 Gy additionally triggering proinflammatory responses. This first genome-wide RNA-seq study of ex vivo X-ray-exposed human blood reveals novel radiosensitive genes, transcription factors, and pathways, enhancing the understanding of the consequences of diagnostic, therapeutic, or accidental exposures on the highly radioresponsive hematological system.

biophysics↗