title: AhR-dependent 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in human neuronal cell line SHSY5Y.
abstract: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a xenobiotic agent with high persistency that induces neurotoxic effects altering neurodevelopment and behavior. The molecular mechanisms and the signaling pathways involved in TCDD-mediated neurotoxicity, together with the search of its molecular targets in neurons are under intense study. We have previously shown that high nanomolar concentrations of TCDD for incubation times of minutes induce apoptosis in SHSY5Y human neuroblastoma cells by the disruption of calcium homeostasis, affecting membrane structural integrity. In this work, we have analyzed the effect of low nanomolar concentrations of TCDD for incubation times of hours to define the role of aryl hydrocarbon receptor which can be activated at those concentrations. TCDD induces toxicity in SHSY5Y human neuroblastoma cells under these experimental conditions with an EC50value of approximately 3nM at 24h of incubation time. Transient transfection of a hairpin RNA for AhR protects against TCDD neurotoxicity, suggesting that AhR is mediating the dioxin effect. Altogether, these results support the hypothesis that TCDD toxicity in SHSY5Y neuroblastoma cells depends on dioxin concentration and time of incubation, with a main role of aryl hydrocarbon receptor at low nanomolar TCDD concentrations.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071-Badajoz, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Morales-Hernández
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071-Badajoz, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Corrales-Redondo
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071-Badajoz, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Marcos-Merino
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071-Badajoz, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: González-Rico
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071-Badajoz, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Sánchez-Martín
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071-Badajoz, Spain. Electronic address: jmmerino@unex.es.
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Merino
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
chemical_list: D000975:Antioxidants; D009498:Neurotoxins; D000072317:Polychlorinated Dibenzodioxins; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D013267:Stilbenes; D053148:Caspase 3; D000077185:Resveratrol
keywords: AhR; Human neuronal cell line SHSY5Y; Neurotoxicity; TCDD