Abstract
Benzo[a]pyrene (B[a]P) is neurotoxic, however, the mechanisms remain unclear and there is no effective prevention. Available evidence suggests a role of DNA methylation in B[a]P-induced neurotoxicity. This study investigated the brain-derived neurotrophic factor (BDNF) IV methylation in the development of and aspirin intervention against B[a]P's neurotoxicity in mice and HT22 cells. Mice were intraperitoneally treated with solvent or B[a]P (0.5, 2, and 10 mg/kg b.w.) for 60 days. An intervention group was treated simultaneously with B[a]P (10 mg/kg, i.p.) and aspirin (10 mg/kg, daily water-drinking). The treated mice showed a dose-dependent cognitive and behavioral impairment, and cerebral cell apoptosis, which were alleviated by aspirin co-treatment. Following B[a]P treatment, DNA methyltransferase (DNMTs) and BDNF IV hypermethylation were increased in the cerebral cortex of mice compared to controls, while significant decreases were found in BDNF IV and BDNF mRNA, and BDNF protein levels. Aspirin co-treatment rescued DNMTs activation and BDNF IV hypermethylation, and mitigated the recession in BDNF mRNA and protein induced by B[a]P treatment. Similar results were shown in HT22 cells. These findings reveal a critical role of BDNF IV methylation in the neurotoxicity of B[a]P, and demonstrate a promising prevention of aspirin against B[a]P-induced cognitive impairment via inhibiting BDNF IV hypermethylation.