Back to Search Start Over

Thimerosal induces apoptosis in a neuroblastoma model via the cJun N-terminal kinase pathway.

Authors :
Herdman ML
Marcelo A
Huang Y
Niles RM
Dhar S
Kiningham KK
Source :
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2006 Jul; Vol. 92 (1), pp. 246-53. Date of Electronic Publication: 2006 Apr 19.
Publication Year :
2006

Abstract

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 (0-10 microM) showed an increase in the phosphorylated (active) form of JNK and cJun with 5 and 10 microM 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 (0-2.5 microM) 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.

Details

Language :
English
ISSN :
1096-6080
Volume :
92
Issue :
1
Database :
MEDLINE
Journal :
Toxicological sciences : an official journal of the Society of Toxicology
Publication Type :
Academic Journal
Accession number :
16624850
Full Text :
https://doi.org/10.1093/toxsci/kfj205