Diethylhexyl phthalate induces anxiety-like behavior and learning and memory impairment in mice probably by damaging blood-brain barrier

Abstract

To investigate the effects of diethylhexyl phthalate (DEHP) exposure on anxiety-like behaviors and learning and memory ability in mice and explore the underlying mechanism. Forty male ICR mice were randomized equally into control group (0 mg/kg) and 10, 50 and 100 mg/kg DEHP exposure groups, in which the mice were exposed to DEHP at the indicated doses by gavage for 4 weeks. After the treatments, the mice were assessed for behavioral changes using open filed test, elevated plus-maze and Morris water maze test. Brain tissues were collected from the mice for determination of malondialdehyde (MDA) content, pathologies and expressions of ZO-1 and occludin in the hippocampus. Compared with the control group, the mice with DEHP exposure for 4 weeks exhibited no significant body weight change (P>0.05) but presented with obvious behavioral changes, manifested by reduced movement distance (P < 0.05) and time spent in the center of the open field (P < 0.05), reduced movement distance (P < 0.05) and time spent in the open arm of the elevated maze (P < 0.05), significantly increased latency of searching for the platform (P < 0.05), and decreased frequency of crossing the platform (P < 0.05). HE staining showed obvious vertebral cell death in the hippocampal CA1 to CA3 regions of the mice with DEHP exposure. The exposed mice showed significantly increased MDA content and decreased expressions of ZO-1 and occludin at both the mRNA and protein levels in the hippocampus (P < 0.05 or 0.01). Multivariate linear regression analysis suggested a close correlation between anxiety-like behaviors and learning and memory abilities in DEHP-exposed mice. DEHP exposure may cause damages of the blood-brain barrier and the pyramidal cells in the hippocampus of mice, thereby inducing anxiety-like behaviors and learning and memory impairment.