Abstract
Lead (Pb), depositing primarily in astroglia in the brain, is a well-known neurotoxicant and a risk factor for neurologic disorders. Pb has been reported to induce oxidative stress by probably the disturbance of copper (Cu) homeostasis in astroglia. Thus, we hypothesized that Pb-induced oxidative stress is initiated by interfering with Cu transporter in astroglia. In this study, we observed Pb-induced oxidative stress as indicated by reactive oxygen species (ROS) augmentation and GRP78 and GRP94 protein induction, and it was parallel to Cu accumulation intracellularly by Pb. To further address Cu transporter as a potential Pb target, a heavy metal-binding (HMB) domain of Cu-transporting ATPase (Atp7a) was overexpressed and purified. Evidence showed that one molecule of HMB chelated 11 Pb ions or seven Cu ions and that Pb competed with Cu for binding to HMB. These findings suggest that Pb-induced oxidative stress results from the impairment of Cu metabolism by Pb targeting of Atp7a.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphatases / metabolism*
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Animals
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Astrocytes / drug effects
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Astrocytes / metabolism*
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Blotting, Western
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Cation Transport Proteins / metabolism*
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Cells, Cultured
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Copper / metabolism
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Copper-Transporting ATPases
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Electrophoresis, Polyacrylamide Gel
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Escherichia coli / metabolism
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HSP70 Heat-Shock Proteins / metabolism
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Heat-Shock Proteins / metabolism
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Lead / metabolism
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Lead / pharmacology*
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Mass Spectrometry
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Membrane Proteins / metabolism
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Molecular Chaperones / metabolism
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Oxidative Stress / drug effects
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Oxidative Stress / physiology*
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Protein Binding / drug effects
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism
Substances
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Cation Transport Proteins
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GRP78 protein, rat
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HSP70 Heat-Shock Proteins
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Heat-Shock Proteins
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Membrane Proteins
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Molecular Chaperones
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Reactive Oxygen Species
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glucose-regulated proteins
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Lead
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Copper
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Adenosine Triphosphatases
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Atp7a protein, rat
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Copper-Transporting ATPases