Chronic Low‐Dose Unsymmetrical Dimethylhydrazine Exposure in Rats: Multiorgan Mechanisms and Biomarker Identification

Unsymmetrical dimethylhydrazine (UDMH), a highly toxic rocket propellant with known multiorgan effects, requires urgent characterization of its chronic low-dose toxicity. Using an integrated approach including exploratory transcriptomics (n = 3/group) and metabolomic (n = 4/group) approaches in male Sprague-Dawley rats exposed to high-dose UDMH concentrations (100 ppm (v/v), 4 h/day, 5 days/week for 60 days), we delineated organ-specific injury mechanisms and identified candidate systemic biomarkers. Histopathological assessment revealed significant pulmonary injury (62.5% incidence of focal hemorrhage, p = 0.015; inflammatory focus density: 8.3 ± 1.7 foci/mm²) and renal injury (tubular basophilia index: 1.8 ± 0.4, p < 0.001). Integrated multiomics analysis identified a mechanistically interconnected biomarker triad: (1) hepatic Cyp4a1 upregulation (log₂FC = 4.7), indicating PPARα-mediated adaptive detoxification; (2) elevated serum taurine (1.27-fold, p < 0.05), reflecting mitochondrial compensatory responses; and (3) increased urinary L-DOPA (3.1-fold, false discovery rate [FDR] < 0.05), signifying neuroendocrine dysregulation. Together, these core biomarkers delineate the pathophysiology of chronic UDMH toxicity, characterized by PPARα-driven detoxification intersecting with mitochondrial stress adaptation and catecholaminergic disruption across organ systems. To our knowledge, this is the first integrated multiomics study of chronic UDMH exposure, establishing a mechanistic framework for toxicity and highlighting pulmonary-renal pathology, serum taurine, and hepatic Cyp4a1 as key indicators for developing future risk assessment strategies.