Dose-Dependent Activation of p53 signaling pathway in Whole Blood and Small Intestine of Mice Exposed to 60 Co Gamma Radiation

Abstract

Ionizing radiation activates the p53 pathway and triggers downstream apoptotic responses, which play a critical role in radiation-induced tissue injury. This study investigates the dose-dependent activation of the p53 pathway in whole blood and small intestine of BALB/C mice exposed to 60 Co gamma radiation at doses of 0, 1, 2, 4, and 8 Gy. Transcriptome sequencing was performed on both tissues collected at day 1 post-irradiation. Differential expression analysis revealed a dose-dependent increase in the number of differentially expressed genes (DEGs) in both tissues. KEGG pathway enrichment analysis identified significant enrichment of the p53 pathway in both whole blood and small intestine at the 8 Gy dose. In whole blood, p53 pathway enrichment scores increased progressively with dose, reaching the highest value of 8.89 at 8 Gy, with 38 enriched genes. In the small intestine, p53 pathway showed a threshold effect, becoming significantly enriched at 2 Gy but showing decreased relative enrichment at higher doses due to activation of broader transcriptional responses. Furthermore, expression analysis of key pro-apoptotic genes downstream of p53—including Bax, Noxa (Pmaip1), PUMA (Bbc3), PAG608 (Zmat3), DR5 (Tnfrsf10b), and IGF (Igf1)—demonstrated dose-dependent upregulation in both tissues, with distinct dose-response thresholds for individual genes. Quadratic polynomial fitting confirmed strong dose-effect relationships for Zmat3, DR5, Bax, and PUMA in the small intestine (R 2 = 0.9726, 0.8697, 0.8915, and 0.9138, respectively). These findings provide comprehensive transcriptome evidence for tissue-specific and dose-dependent activation of p53-mediated apoptotic signaling following gamma radiation exposure, contributing to a better understanding of radiation-induced molecular mechanisms for potential biodosimetry applications.