Dose-dependent reproductive toxicity and transcriptomic responses to ionizing radiation in male BALB/c mice

This study systematically investigated the dose-dependent effects of ionizing radiation (3 Gy, 5 Gy, 8 Gy) on male BALB/c mice, focusing on reproductive toxicity and oxidative-inflammatory crosstalk. Histopathological analysis revealed progressive testicular atrophy, seminiferous epithelium thinning, and epididymal sperm reduction, with 8 Gy exposure causing 66.46% and 73.88% declines in sperm concentration and viability, respectively. Radiation induced significant oxidative imbalance, evidenced by depleted antioxidant enzymes (SOD, GSH-Px, CAT) and elevated lipid peroxidation (MDA, P < 0.05). Pro-inflammatory cytokines (IL-6, TNF-Alpha) were upregulated, while anti-inflammatory factors (IL-10, TGF-Beta) and immune markers (IgM, C3, C4) decreased dose-dependently. Transcriptomic profiling identified 11,553 differentially expressed genes (DEGs), with significant enrichment in apoptosis, PPAR signaling, and lysosomal pathways. Notably, PI3K/AKT emerged as a key regulatory cluster within cancer-related pathways, suggesting its non-canonical role in stress-induced cellular responses. KEGG analysis highlighted systemic immune dysregulation, including complement cascade disruption. The 5 Gy dose uniquely activated lysosomal pathways (GO:0005764) and proteostasis compensation. These findings elucidate that radiation toxicity arises from oxidative-inflammatory crosstalk and signaling dysregulation, with PPAR and PI3K/AKT pathways identified as potential therapeutic targets. This study provides critical molecular insights into radiation-induced reproductive damage and advocates for antioxidant, anti-inflammatory, and PI3K/AKT-targeted interventions to mitigate toxicity, offering a foundation for future radioprotection strategies.