ToxSci Advance Access originally published online on February 16, 2006
Toxicological Sciences 2006 91(1):184-191; doi:10.1093/toxsci/kfj137
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Zinc Deficiency Increases the Susceptibility of Human Neuroblastoma Cells to Lead-Induced Activator Protein-1 Activation
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* Department of Nutrition, University of California, Davis, Davis, California 95616; and Department of Environmental Toxicology, University of California, Davis, Davis, California 95616
Received January 10, 2006; accepted February 11, 2006
Lead (Pb2+) is a major environmental pollutant that has severe adverse effects on the nervous system. Similar human populations are at risk of suffering both Pb2+ toxicity and zinc (Zn) deficiency. Thus, in the present study we investigated whether Zn deficiency can increase the susceptibility of human neuroblastoma IMR-32 cells to Pb2+-induced oxidative stress which could trigger the activation of the mitogen-activated protein kinases (MAPKs) c-Jun-N-terminal kinase (JNK) and p38 and subsequently activate transcription factor activator protein-1 (AP-1). After 24 h of incubation, 5–50µM Pb2+ caused a decrease in cell viability that was markedly higher in the Zn-deficient cells compared to controls. Pb caused a time (2–24 h) and dose (5–50µM)–dependent increase of cell oxidants, with a significantly higher effect in the Zn-deficient cells. Pb2+ treatment triggered the activation of JNK and p38, measured as the phosphorylation of JNK and p38, only in cells incubated in the Zn-deficient media. The exposure to Pb2+ (2–24 h) led to a higher AP-1 DNA-binding activity and AP-1–dependent gene transactivation, only in the Zn-deficient cells. Results show that Zn deficiency can increase the cytotoxicity of Pb2+ and the susceptibility of neurons to Pb2+-induced oxidative stress, leading to JNK and p38 phosphorylation and, subsequently, AP-1 activation.
Key Words: lead; zinc; AP-1; oxidative stress; MAPK.