Di-n-butyl phthalate exposure negatively influences structural and functional neuroplasticity via Rho-GTPase signaling pathways. (July 2017)

• Record Type: Journal Article
• Authors: Ding, Yuemin; Lu, Lingchao; Xuan, Chengkai; Han, Jiajv; Ye, Shumin; Cao, Tingting; Chen, Weibo; Li, Aiqing; Zhang, Xiong
• Is Part Of: Food and chemical toxicology. Volume 105(2017)
• Page Start: 34
• Page End: 43
• Publication Date: 2017-07
• Subjects: Di-n-butyl phthalate (DBP) -- Neuroplasticity -- Rho-GTPase; ANOVA analysis of variance -- BBP benzyl butyl phthalate -- CREB cyclic adenosine monophosphate response element binding protein -- DBP di-n-butyl phthalate -- DiBP diisobutyl phthalate -- DEHP di(2-ethylhexyl) phthalate -- DMSO dimethyl sulfoxide -- DIV days in vitro -- DMEM Dulbecco's modified Eagle's medium -- ECL enhanced chemiluminescent -- FBS fetal bovine serum -- GAPDH glyceraldehyde-3-phosphate dehydrogenase -- GST Glutathione-S-transferase -- LTP long-term potentiation -- LIMK LIM kinase -- MWM Morris water maze -- PAEs phthalic acid esters -- PAK p21-activated kinase -- PVDF polyvinylidene fluoride -- ROCK Rho-associated protein kinase -- SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electropheresis; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2017.03.057
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: 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°mg/kg/d) for 5 weeks. Chronic exposure to high concentrations of DBP (250°mg/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 Rac1/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°ng/ml, 1, 10, or 100°μg/ml) for 72 hours. Moreover, acute exposure to high concentrations of DBP (100°μg/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. Graphical abstract: Highlights: Chronic oral exposure to DBP caused the impairment of spatial learning ability in adult male mice. DBP exposure inhibited the activity of Rac1/PAK1/LIMK1 and eventually inhibited cofilin activity. DBP incubation inhibited neurite outgrowth and migration in neuronal cells, which was revised by a ROCK inhibitor.