Benzo[a]pyrene (B[a]P) is recognized as a highly neurotoxic contaminant, however, the underlying mechanisms remain poorly understood. This study aimed to examine the alterations in erythropoietin-producing hepatocyte receptors (EphA4, EphA5) and their ligands (Ephrin A5) in the context of B[a]P-induced neurotoxicity, both in vivo and in vitro. A total of forty male mice were administered intraperitoneal injections of either a solvent (peanut oil) or a B[a]P solution (at doses of 0.5, 2, and 10 mg/kg) over a period of 60 days, once every other day. Following 30 exposures, the mice were subjected to exploratory behavioral assessments, transmission electron microscopy for hippocampal ultrastructural alterations, and western blotting to measure synapse-associated proteins (SYP, PSD95), as well as EphA4, EphA5, and Ephrin A5 proteins in the cerebral cortex. Parallel experiments were conducted using HT22 hippocampal neuronal cells. The results indicated that B[a]P treatment led to impairments in spatial cognitive function and spontaneous behavior, abnormal synaptic remodeling, and reduced SYP and PSD95 protein levels. Notably, compared to the control group, there was a marked increase in the protein levels of EphA4 and EphA5 in the cerebral cortex of mice following B[a]P treatment at mid and high doses, while Ephrin A5 protein level was significantly depressed at high dose. Additionally, in HT22 cells treated with B[a]P (0, 0.2, 2, and 20 μM) for 48 h, both cell viability and cell numbers exhibited a significant decline, accompanied by abnormal neuronal synaptic remodeling. In comparison to the control cells, EphA4 and EphA5 protein levels were significantly elevated in HT22 cells following B[a]P treatment, whereas Ephrin A5 protein levels were notably suppressed. These findings suggest that B[a]P may induce neurotoxicity through the disruption of synaptic remodeling via the EphA/EphrinA5 signaling pathway.
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