ToxSci Advance Access originally published online on April 19, 2006
Toxicological Sciences 2006 92(1):246-253; doi:10.1093/toxsci/kfj205
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Thimerosal Induces Apoptosis in a Neuroblastoma Model via the cJun N-Terminal Kinase Pathway
Departments of * Pharmacology, Physiology, and Toxicology and Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia 25704; and Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536
Received January 9, 2006; accepted April 17, 2006
The cJun N-terminal kinase (JNK)-signaling pathway is activated in response to a variety of stimuli, including environmental insults, and has been implicated in neuronal apoptosis. In this study, we investigated the role that the JNK pathway plays in neurotoxicity caused by thimerosal, an ethylmercury-containing preservative. SK-N-SH cells treated with thimerosal (0–10µM) showed an increase in the phosphorylated (active) form of JNK and cJun with 5 and 10µM thimerosal treatment at 2 and 4 h. To examine activator protein-1 (AP-1) transcription, cells were transfected with a pGL2 vector containing four AP-1 consensus sequences and then treated with thimerosal (0–2.5µM) for 24 h. Luciferase studies showed an increase in AP-1 transcriptional activity upon thimerosal administration. To determine the components of the AP-1 complex, cells were transfected with a dominant negative to either cFos (A-Fos) or cJun (TAM67). Reporter analysis showed that TAM67, but not A-Fos, decreased AP-1 transcriptional activity, indicating a role for cJun in this pathway. To assess which components are essential to apoptosis, cells were treated with a cell-permeable JNK inhibitor II (SP600125) or transfected with TAM67, and the downstream effectors of apoptosis were analyzed. Cells pretreated with SP600125 showed decreases in activation of caspases 9 and 3, decreases in degradation of poly(ADP-ribose) polymerase (PARP), and decreased levels of proapoptotic Bim, in comparison to cells treated with thimerosal alone. However, cells transfected with TAM67 showed no changes in those same components. Taken together, these results indicate that thimerosal-induced neurotoxicity occurs through the JNK-signaling pathway, independent of cJun activation, leading ultimately to apoptotic cell death.
Key Words: thimerosal; mercury; neurotoxicity; JNK; cJun; Bim.
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