Academic journal article Environmental Health Perspectives

Arsenic Inhabits Neurite Outgrowth by Inhibiting the LKB1-AMPK Signaling Pathway

Academic journal article Environmental Health Perspectives

Arsenic Inhabits Neurite Outgrowth by Inhibiting the LKB1-AMPK Signaling Pathway

Article excerpt

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 ([less than or equal to] 5 [micro]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-Ctl 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.

KEY WORDS: AMPK, arsenic, developmental neurotoxicity, LKB1, neurite outgrowth, neuro-2a neuroblastoma cell, ROS. Environ Health Perspect 118:627-634 (2010). doi:10.1289/ehp.0901510 [Online 22 December 2009]


Underground water in many regions of the world is contaminated with arsenic (As), and the resulting toxicity has created a major environmental and public health problem in the affected regions. Chronic As exposure can cause many diseases, including neurodevelopmental disorders and brain disease. Arsenic--along with As compounds--is one of the five industrial chemicals proven to cause neurodevelopmental disorders among thousands of known chemicals (Grandjean and Landrigan 2006). In rats, As exposure during the rapid brain-growth period causes faulty migration, delayed maturation, and alteration in nuclear area measurements of Purkinje cells in the cerebellum and impaired brain structural organization and the shape of fiber tracts and axons in the striatum (Dhar et al. 2007; Rfos et al. 2009). Although accumulating evidence for neurodevelopmental neurotoxicity of As is established, the causative mechanism remains unclear. The toxic effects of As on children have generally been overlooked, and regulatory action does not emphasize the need to protect the developing brain against this neurotoxic substance (Mukherjee et al. 2006).

Adenosine monophosphate-activated kinase (AMPK) is an important integrator of signals that control cellular energy balance through the regulation of multiple biochemical pathways (Hardie et al. 1999). Recent studies have suggested that AMPK also regulates cell structure and polarity, cell division, and normal growth and development (Dasgupta and Milbrandt 2009; Lee et al. 2007). AMPK helps maintain genomic integrity in neuron precursors and the structure and function of mature neurons in Drosophik (Lee et al, 2007). Loss of AMPK activity causes neurodegeneration in Drosophila (Spasic et al. 2008) and structural and functional brain abnormalities in AMPK-mutant mice (Dasgupta and Milbrandt 2009). The activation of AMPK contributes to the stimulating effect of resveratrol on neurite outgrowth in neurons (Dasgupta and Milbrandt 2007). …

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