Elucidating 6PPD-Q-induced metabolic reprogramming and systemic injury via ultrasensitive breathomics.

Although 6PPD-quinone (6PPD-Q), a pervasive tire-derived contaminant, poses emerging health risks, its systemic toxicity mechanisms remain poorly understood; effective noninvasive monitoring tools are still lacking. We combined ultrasensitive photoinduced associative ionization time-of-flight mass spectrometry (PAI-TOFMS) with multi-organ transcriptomics and serum metabolomics to mechanistically assess 6PPD-Q-induced toxicity in mice. We identified a robust and highly sensitive five-analyte breath panel associated with organ-level molecular perturbations. Mechanistic integration suggests that acetaldehyde is associated with a hepatic metabolic reprogramming syndrome that dysregulates steroid biosynthesis and with oxidative stress-driven transcriptional signatures of genotoxic stress. Dimethyl disulfide is associated with perturbation of systemic sulfur metabolism and correlates with hepatic glutathione depletion and redox imbalance. In the kidneys, trimethylamine is associated with compromised clearance and metabolic stagnation, potentially related to PPAR signaling suppression. In the lungs, monochloramine and 3-buten-2-one are associated with immune infiltration and membrane lipid peroxidation, respectively. By establishing a cohesive "breath-blood-organ" framework, we demonstrate that these exhaled signatures are consistent with internal tissue pathology. This study elucidates the multi-organ toxicity of 6PPD-Q via a metabolic-genotoxic axis and provides a validated noninvasive toolkit for future environmental epidemiology and population health screening.