Unsymmetrical dimethylhydrazine induces dose-dependent liver toxicity in rats via oxidative stress and PI3K/Akt pathway-mediated apoptosis

Unsymmetrical dimethylhydrazine (UDMH), a hypergolic propellant widely used in aerospace, is classified as a Group 2B carcinogen. Although UDMH induces dose-dependent hepatotoxicity, the underlying mechanisms remain unclear. This study tested the hypothesis that PI3K/Akt-mediated apoptosis drives UDMH-induced subacute liver injury. Male Sprague-Dawley rats were exposed to filtered air (control), 141 ± 10 ppm (low-dose), or 282 ± 10 ppm (high-dose) UDMH via inhalation (1 h/d, 5 d/wk) for 4 weeks. UDMH exposure caused mild weight loss and elevated serum ALT, ALP, and TBA while reducing ALB, indicating hepatic dysfunction. It also induced oxidative stress, evidenced by decreased T-SOD, GSH, and CAT activities, increased MDA levels, and upregulated proinflammatory cytokines (IL-1β, IL-6, TNF-α). Histology revealed dose-dependent inflammatory cell infiltration and hepatic sinusoidal hemorrhage with severe cytoplasmic disruption; TUNEL staining confirmed increased hepatocyte apoptosis. RNA-seq identified 1,700 DEGs enriched in PI3K-Akt and apoptosis pathways. Western blotting confirmed dose-dependent inhibition of PI3K/Akt signaling (reduced p-PI3K/PI3K and p-Akt/Akt ratios) and apoptosis activation (elevated Bax/Bcl-2 and cleaved caspase-3/caspase-3 ratios). Notably, oxidative stress preceded PI3K/Akt suppression, suggesting redox imbalance triggers PI3K/Akt-dependent hepatocyte death. These findings establish PI3K/Akt-mediated apoptosis as a core mechanism of UDMH hepatotoxicity, providing a rationale for targeting this pathway to protect aerospace workers.