title: Di-n-butyl phthalate exposure negatively influences structural and functional neuroplasticity via Rho-GTPase signaling pathways.
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.
authors.affiliation: Department of Clinical Medicine, School of Medicine, Zhejiang University City College, 50 Huzhou Street, Hangzhou 310015, China. Electronic address: dingyuemin@zucc.edu.cn.
authors.forename: Yuemin
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Clinical Medicine, School of Medicine, Zhejiang University City College, 50 Huzhou Street, Hangzhou 310015, China. Electronic address: 654133513@qq.com.
authors.forename: Lingchao
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Clinical Medicine, School of Medicine, Zhejiang University City College, 50 Huzhou Street, Hangzhou 310015, China. Electronic address: 1145645445@qq.com.
authors.forename: Chengkai
authors.initials: C
authors.lastname: Xuan
authors.affiliation: Department of Clinical Medicine, School of Medicine, Zhejiang University City College, 50 Huzhou Street, Hangzhou 310015, China. Electronic address: 759666695@qq.com.
authors.forename: Jiajv
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Clinical Medicine, School of Medicine, Zhejiang University City College, 50 Huzhou Street, Hangzhou 310015, China. Electronic address: 2932512368@qq.com.
authors.forename: Shumin
authors.initials: S
authors.lastname: Ye
authors.affiliation: Department of Clinical Medicine, School of Medicine, Zhejiang University City College, 50 Huzhou Street, Hangzhou 310015, China. Electronic address: 526366839@qq.com.
authors.forename: Tingting
authors.initials: T
authors.lastname: Cao
authors.affiliation: Department of Clinical Medicine, School of Medicine, Zhejiang University City College, 50 Huzhou Street, Hangzhou 310015, China. Electronic address: 384032553@qq.com.
authors.forename: Weibo
authors.initials: W
authors.lastname: Chen
authors.affiliation: Gastroenterology Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China. Electronic address: li_aq2003@aliyun.com.
authors.forename: Aiqing
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Basic Medical Science, Zhejiang University School of Medicine, C541 Medical Research Building, 866 Yu Hang Tang Road, Hangzhou 310058, China. Electronic address: xiongzhang@zju.edu.cn.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003993:Dibutyl Phthalate / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D003993:Dibutyl Phthalate; D020741:rho GTP-Binding Proteins
keywords: Di-n-butyl phthalate (DBP); Neuroplasticity; Rho-GTPase