Di-n-butyl phthalate exposure negatively influences structural and functional neuroplasticity via Rho-GTPase signaling pathways

Di-n-butyl phthalate (DBP) has been reported to cause disruptions in hippocampal plasticity, but its specific mechanism has not yet been ascertained. In this research, a mouse model of chronic DBP exposure was generated by intragastric administration of DBP (10, 50, or 250 degrees mg/kg/d) for 5 weeks. Chronic exposure to high concentrations of DBP (250 degrees Ing/kg/d) induced a spatial learning deficit in the Morris water maze in male mice. By determining the activity of Rho-GTPase signaling pathways in the hippocampal tissues, we found that DBP exposure inhibited the activity of Racl/PAK1/LIMK1 but activated RhoA/ROCK/LIMK2 signaling and eventually suppressed cofilin activity by phosphorylation. Consistent with this, the differential activation was also observed in the acute exposure model of neuronal cells generated by incubation with DBP (100 degrees ng/ml, 1, 10, or 100 degrees mu g/ml) for 72 hours. Moreover, acute exposure to high concentrations of DBP (100 degrees mu g/ml) altered cell morphology by inhibiting neurite outgrowth. A ROCK inhibitor, but not inhibitors of Rac1 or PAK1, reversed the inhibition of DBP to the activity of cofilin and neurite outgrowth in cells. These findings provide the first evidence that DBP exposure results in impairment of neuroplasticity by differential regulation of Rho-GTPase signaling pathways. (C) 2017 Elsevier Ltd. All rights reserved.