Arsenic inhibits neurite outgrowth by inhibiting the LKB1--AMPK signaling pathway.
Background: Arsenic (As) is an environmental pollutant that induces numerous pathological effects, including neurodevelopmental disorders. Objectives and Methods: We evaluated the role of the LKB1-AMPK pathway in As-induced developmental neurotoxicity using Neuro-2a (N2a) neuroblastoma cells as a mo...
| Publicado en: | Environmental Health Perspectives Vol. 118; no. 5; pp. 627 - 635 |
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| Autores principales: | , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
National Institute of Environmental Health Sciences
May2010
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=105068547&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 105068547 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00916765 3B5 jtl: Environmental Health Perspectives issn: 00916765 maglogo: N pubinfo: dt: May2010 vid: 118 iid: 5 pid: 56539 pub: National Institute of Environmental Health Sciences place: Research Triangle Park, North Carolina artinfo: ui: 105068547 2010731758 10.1289/ehp.0901510 NLM20439172 PMC2866677 105068547 ppf: 627 ppct: 8 formats: fmt: @attributes: type: P tig: atl: Arsenic inhibits neurite outgrowth by inhibiting the LKB1--AMPK signaling pathway. aug: au: Wang X Meng D Chang Q Pan J Zhang Z Chen G Ke Z Luo J Shi X affil: Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky sug: subj: Arsenic Adverse Effects Drug Toxicity Neurons Drug Effects Analysis of Variance Animal Studies Cattle Cell Differentiation Drug Effects Data Analysis Software Enzymes Metabolism Funding Source Neuroblastoma Post Hoc Analysis Tissue Culture Techniques ab: Background: Arsenic (As) is an environmental pollutant that induces numerous pathological effects, including neurodevelopmental disorders. Objectives and Methods: We evaluated the role of the LKB1-AMPK pathway in As-induced developmental neurotoxicity using Neuro-2a (N2a) neuroblastoma cells as a model of developing neurons. Results: The addition of low concentrations of As (<= 5 [mu]M) during differentiation caused an inhibitory effect on the neurite outgrowth in N2a cells in the absence of cell death. Activation of adenosine monophosphate-activated kinase (AMPK) induced by retinoic acid in differentiating cells was blocked by As. Pretreatment with the AMPK-specific activator 5-aminoimidazole- 4-carboxamide riboside or overexpression of a constitutively active AMPK-[alpha]1 plasmid reversed As-induced inhibition of neurite outgrowth. The activation of LKB1 (serine/threonine kinase 11), a major AMPK kinase, was also suppressed by As by inhibiting both the phosphorylation and the translocation of LKB1 from nucleus to cytoplasm. Antioxidants, such as N-acetyl cysteine and superoxide dismutase, but not catalase, protected against As-induced inactivation of the LKB1-AMPK pathway and reversed the inhibitory effect of As on neurite outgrowth. Conclusions: Reduced neurite outgrowth induced by As results from deficient activation of AMPK as a consequence of a lack of activation of LKB1. Oxidative stress induced by As, especially excessive superoxide, plays a critical role in blocking the LKB1-AMPK pathway. Our studies provide insight into the mechanisms underlying As-induced developmental neurotoxicity, which is important for designing a new strategy for protecting children against this neurotoxic substance. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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