Objective  To observe the changes of telomere length and p53 and p21 protein expression levels in mice exposed to different time and doses, and to explore the role of related pathways protein in benzo［a］pyrene in learning and memory impairment.  Methods  Ninety healthy male C57 mice, 30 in each batch, were exposed for 1 month, 2 months and 3 months respectively. Each batch was set with blank control group, solvent control group, 1.00 mg/kg, 2.50 mg/kg and 6.25 mg/kg benzo［a］pyrene-treated groups, 6 in each group, inoculated intraperitoneally every other day. Learning and memory ability was detected by Morris water maze test, ELISA was used to detect the content of benzo［a］ pyrene-7, 8-dihydrodiol-9,10-epoxide-DNA（BPDE-DNA）adduct in mice plasma. There was no significant difference in the relative telomere length of the mice at 1 mouth of each group. The length in mice after treated for 2 and 3 months were significantly shorter than that of the non-infected group (P<0.05). And the plasma BPDE-DNA adduct content in each exposed group was negatively correlated with the relative telomere length. Western blotting was used to detect the expression of p53-p21 related pathway protein and neural stem cell proliferation and differentiation related proteins Nestin and βⅢ-tubulin in mouse hippocampus. Relative telomere length was detected by Real-time PCR.  Results The escape latency of mice in each exposed group was significantly prolonged, and the times of crossing platforms was significantly reduced. BPDE-DNA adduct was not detected in the non-dose group and in the exposed group showed an upward trend (P<0.05). Compared with the non-dose group, the expression levels of p53 and p21 in the exposed group increase with the dose of the drug (P<0.05). When the dose was 1.0 mg/kg, the expression level of Nestin did not significantly increase. The expression level of Nestin increased in the remaining exposure groups (P<0.05), and the expression level of Nestin was lower than that in the 1.0 mg/kg and 2.5 mg/kg groups at the dose of 6.25 mg/kg for 3 months (P<0.05). At 1 month, there was no significant difference in the expression of βⅢ-tubulin between the exposed and non-infected groups. At 2 and 3 months, the expression of βⅢ-tubulin in the exposed group decreased (P<0.05).   Conclusion  Intraperitoneal injection of benzo［a］pyrene can induce DNA damage and telomere shortening due to BPDE-DNA adduct formation, which leads to activation of p53-p21 signaling pathway. Telomere shortening and p53-p21 signaling pathway activation-mediated DNA damage response may be important mechanisms for inhibiting proliferation and differentiation of hippocampal neurons.