Subchronic ozone exposure leads to multi-organ injuries with differential reversibility in male C57BL/6 J mice.

Ozone, a prevalent environmental pollutant, poses significant risks to human health. This study systematically evaluates the impact of subchronic ozone exposure on multiple organs using three-month-old male C57BL/6 J mice exposed to 0.5 or 2.0 ppm ozone for 12 weeks, followed by 4-week recovery period. Subchronic ozone exposure caused systemic damage, including weight loss, inflammation, oxidative stress, and dyslipidemia, with varying degrees of reversibility. Comprehensive histopathological and functional analyses revealed dose-dependent injuries, organ-specific response patterns, and varying recovery capacities within a 4-week cessation of exposure. The lung demonstrated the highest susceptibility with dose-dependent damage and high reversibility. In contrast, the liver, kidneys, and brain, exhibited milder yet largely irreversible damage, particularly at 2.0 ppm. Transcriptomic analyses identified high reversibility in lung inflammation pathways, persistent metabolic dysregulation in the liver and kidneys, neurodegeneration-related perturbations in the brain with minimal recovery capacity. Furthermore, common molecular drivers, such as oxidative stress and inflammation, were identified across all organs, revealing both unique and shared mechanisms of injury and recovery. These findings underscore the systemic nature of ozone toxicity and the need for targeted interventions. Persistent dyslipidemia and metabolic dysregulation in the liver and kidneys emphasize the necessity for ongoing monitoring and potential interventions for individuals exposed to elevated ozone levels.