title: Aryl hydrocarbon receptor-dependent induction of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells from mouse.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a prototypical environmental contaminant with neurotoxic properties that alters neurodevelopment and behavior. TCDD is a ligand of the aryl hydrocarbon receptor (AhR), which is a key signaling molecule to fully understand the toxic and carcinogenic properties of dioxin. Much effort is underway to unravel the molecular mechanisms and the signaling pathways involved in TCDD-induced neurotoxicity, and to define its molecular targets in neurons. We have used cerebellar granule cells (CGC) from wild-type (AhR+/+) and AhR-null (AhR-/-) mice to characterize the cell death that takes place in neurons after TCDD toxicity. TCDD induced cell death in CGC cultures from wild-type mice with an EC(50) of 127±21 nM. On the contrary, when CGC neurons from AhR-null mice were treated with TCDD no significant cell death was observed. The role of AhR in TCDD-induced death was further assessed by using the antagonists resveratrol and α-naphtoflavone, which readily protected against TCDD toxicity in AhR+/+ CGC cultures. AhR+/+ CGC cultures treated with TCDD showed nuclear fragmentation, DNA laddering, and increased caspase 3 activity, similarly to what was found by the use of staurosporine, a well-established inducer of apoptosis. Finally, the AhR pathway was active in CGC because TCDD could induce the expression of the target gene cytochrome P450 1A2 in AhR+/+ CGC cultures. All together these results support the hypothesis that TCDD toxicity in CGC neurons involves the AhR and that it takes place mainly through an apoptotic process. AhR could be then considered a novel target in neurotoxicity and neurodegeneration whose down-modulation could block certain xenobiotic-related adverse effects in CNS.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Sánchez-Martín
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Fernández-Salguero
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Merino
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D007211:Indoles; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000502:physiology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D014343:Trypan Blue
chemical_list: D001572:Benzofurans; D004785:Environmental Pollutants; D007211:Indoles; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D013778:Tetrazolium Salts; D013844:Thiazoles; C007293:DAPI; D019388:Cytochrome P-450 CYP1A2; D053148:Caspase 3; C022616:thiazolyl blue; D014343:Trypan Blue; C014211:2,3,7,8-tetrachlorodibenzofuran