Benzo[a]pyrene exposure induces anxiety-like behaviors in the mice through brain metabolic alterations

The deleterious health impacts of polycyclic aromatic hydrocarbons (PAHs) on the population have been extensively substantiated and acknowledged. Mounting evidence underscores that PAH exposure is closely linked to an elevated risk of mental disorders, particularly in populations experiencing occupational and high-level exposure. In this study, we aimed to investigate the mechanisms underlying anxiety-like behaviors induced by different dosages of PAHs, with a concentrated focus on brain region-specific metabolic alterations in mice using various metabolomics approaches. Male C57BL/6 mice were exposed to benzo[a]pyrene (B[a]P), a typical PAH, through gavage at occupational exposure and EPA toxicologically relevant dosages (2.0 and 20.0 mg/kg/day) for 21 days, respectively. Behavioral assessments revealed that occupational exposure to B[a]P induced anxiety-like behaviors in C57BL/6 mice. Meanwhile, elevated serum norepinephrine and corticotropin-releasing hormone further confirmed the anxiety-inducing effects of B[a]P exposure. Metabolomics analysis uncovered dysregulation across various metabolic pathways following B[a]P exposure, encompassing brain neurotransmitter, organic acid, amino acid, lipid, fatty acid, and cholesterol. Anxiety levels and lipid metabolic abnormalities were notably exacerbated at the higher dosage, despite being only a 10-fold increase. Of particular significance, a decrease in lysophosphatidic acid (LPA) and lysophosphatidylserine (LPS) emerged as pivotal indicators of B[a]P neurotoxicity. Spatial-resolved metabolomics further demonstrated distinctive lipid and metabolite profiles across different brain subregions after exposure to B[a]P. Remarkably, alterations were specifically observed in the anxiety-related brain regions, such as the hippocampus, cortex, white matter, and thalamus, varying with exposure dosages. These findings underscore the significance of brain metabolic abnormalities in the development of mental disorders triggered by B[a]P exposure and highlight the need for establishing precise exposure limits of B[a]P to safeguard public mental health.