Ambient NO₂ exposure sex-specifically impairs myelin and contributes to anxiety and depression-like behaviors of C57BL/6J mice

NO₂ is a common indoor and outdoor air pollutant, but its health effects are still controversial. Beside respiratory injury, more epidemiological studies show that inhalation of NO₂ is associated with an increased risk of anxiety and depression. However, the causal relationship at the molecular level remains unclear. In the present study, we exposed adult C57BL/6J mice to NO₂ (2.5 ppm, 5 h/day) for four weeks, and found anxiety and depression-like behaviors in male mice, but not female mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment indicated that differentially expressed genes (DEGs) in the prefrontal cortex and cerebellum were closely associated with signal transduction pathways, such as axon guidance. Importantly, NO₂ inhalation damaged the ultrastructure of myelin sheath and caused the abnormal expression of related genes in males, which partially contributed to mental disorders. We also found that prolactin (Prl), through its anti-inflammatory activity and remyelination, might play a major role in the sex-specific neurobehavioral disorder in male mice caused by NO₂ exposure.