title: 2,3,7,8-TCDD induces neurotoxicity and neuronal apoptosis in the rat brain cortex and PC12 cell line through the down-regulation of the Wnt/β-catenin signaling pathway.
abstract: TCDD exposure has various toxic effects on in the human nervous system resulting in various developmental and behavioral deficits. However the underlying molecular mechanism of TCDD-induced adverse effects on the CNS and associated signaling pathways remains largely unknown. Herein we analyzed acute TCDD exposure in the rat brain cortex to investigate whether misregulation of the Wnt/β-catenin signaling pathway plays a role in neurotoxicity. Western blot and immunohistochemical experiments revealed a significant down-regulation of β-catenin and phospho-glycogen synthase kinase-3β (pSer9-GSK-3β) after TCDD exposure. TUNEL assay results showed apoptosis occurs mainly at day 7 after TCDD treatment. Immunofluorescent labeling indicated that β-catenin was localized mainly in the neurons; co-localization of β-catenin and active caspase-3 was found following TCDD exposure. Further, TCDD exposure decreased the level of pSer9-GSK-3β and β-catenin, and increased apoptosis in the PC12 neuronal cell line in a dose-dependent manner. Interestingly the application of lithium chloride, a GSK-3β inhibitor, reversed the suppressive effect of TCDD on β-catenin in PC12 cells and primary cortical neurons restoring cell viability and protecting cells from apoptosis as compared to untreated controls. Taken together, these results indicate that the canonical Wnt/β-catenin signaling pathway may play an important role in TCDD-induced neurotoxicity and neuronal apoptosis.
authors.affiliation: Department of Nutrition and Food Hygieney, School of Public Health, Nantong University, Nantong 226001, Jiangsu, People's Republic of China.
authors.forename: Guangfei
authors.initials: G
authors.lastname: Xu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wan
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.forename: Yuanye
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Nie
authors.forename: Chun
authors.initials: C
authors.lastname: Cheng
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells; D010766:Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495268:Ctnnb1 protein, rat; D000072317:Polychlorinated Dibenzodioxins; D047428:Protein Kinase Inhibitors; D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C505410:Casp3 protein, rat; D053148:Caspase 3