Hexavalent chromium inhalation exposure induces metabolic reprogramming underlying lung injury and partial endogenous repair in mice.

Hexavalent chromium [Cr(VI)] is a pervasive toxicant in occupational and environmental settings, posing significant respiratory risks, yet the metabolic mechanisms underpinning its pulmonary toxicity and repair remain unclear. In this study, C57BL/6 J mice underwent 28 days of whole‑body inhalation exposure to aerosolized 150 μg/m³ Cr(VI), followed by a two‑week unassisted recovery. Blood chromium (Cr) levels were quantified using inductively coupled plasma mass spectrometry. Lung function, inflammatory cells of bronchoalveolar lavage fluid (BALF), and histopathology were assessed alongside untargeted metabolomics of lung tissue to comprehensively evaluate the effects of Cr(VI) exposure. Cr(VI) inhalation resulted in significant systemic Cr accumulation, alveolar inflammation, wall thickening, and reduced lung elasticity and ventilatory capacity. No significant differences in inflammatory cells counts were observed in BALF between Cr(VI)-exposed and control groups. Metabolomic analysis identified 32 differential metabolites affected by Cr(VI) that were enriched in arachidonic acid, linoleic acid, and pyrimidine pathways, notably elevated prostaglandin E₂, 20-Hydroxyeicosatetraenoic acid, 12-Hydroxyheptadecatrienoic acid (12S-HHT), cytidine, and uridine. The recovery phase ameliorated most functional and histological alterations, and identified glycerophospholipid metabolism and arachidonic acid metabolism as the most significantly perturbed processes. These pathways showed significant depletion of membrane phospholipids and inflammatory mediators, potentially reflecting enhanced lipid membrane remodeling and attenuated inflammatory signaling during lung tissue repair. Correlation analysis highlighted 12S-HHT and distinct phosphatidylcholine species as biomarkers strongly associated with Cr burden and functional decline. These findings elucidate the metabolic perturbations involved in arachidonic acid and glycerophospholipid metabolism underlying Cr(VI)-induced lung injury and natural repair processes. The identified metabolites offer promising targets for biomonitoring and therapeutic intervention.