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.


OBJECTIVE
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 (<or= 5 microM) 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-alpha1 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.
Wang
Xin
X
Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536 , USA.
Meng
Dan
D
Chang
Qingshan
Q
Pan
Jingju
J
Zhang
Zhuo
Z
Chen
Gang
G
Ke
Zunji
Z
Luo
Jia
J
Shi
Xianglin
X
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D001151:Arsenic / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004782:Environmental Health; D004791:Enzyme Inhibitors / Q000633:toxicity; D006801:Humans; D016501:Neurites / Q000187:drug effects* / Q000201:enzymology* / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014874:Water Pollutants, Chemical / Q000633:toxicity*
D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D014874:Water Pollutants, Chemical; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D001151:Arsenic