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PW07 Pesticides and Pharmaceuticals
(PW116) Activation of c-Jun N-terminal /stress-activated protein kinases by endosulfan in HepG2 cells.
Freedman, J.1, Song, M.O.1, 1 Nicholas School of the Environment and Earth Sciences, Duke University, Durham, NC, USA
ABSTRACT- Endosulfan, an organochlorine insecticide, is one of the most commonly used pesticides in agriculture, and a priority pollutant. A causal relationship between long term exposure to this pesticide and the development of non-Hodgkin′s lymphoma has been suggested. Endosulfan has also been reported to induce mitochondrial dysfunction, and oxidative stress in a human T-cell leukemic cell line. The ability of endosulfan to modulate the activities of stress responsive signal transduction pathways and activating protein-1 (AP-1) has not been investigated. In the present study, we investigate whether the mechanism of endosulfan toxicity is related to intracellular oxidative stress and changes in mitogen-activated protein kinases signaling. Our study shows that endosulfan can induce a cellular stress response in HepG2 cells, which is reflected by the increase in c-Jun N-terminal/stress-activated protein kinases (JNK/SAPK) phosphorylation. Endosulfan also causes an increase c-Jun phosphorylation after 24-hour treatment. To investigate the transcriptional response to endosulfan exposure, we performed transient transfection analyses with a rat NAD(P)H:quinone oxidoreductase 1-based chloramphenicol acetyl transferase reporter plasmid. Endosulfan significantly increased antioxidant responsive element (ARE)-mediated transcription. In addition, depletion of glutathione significantly enhanced endosulfan-induced activation of ARE-mediated transcription. To examine the effect of endosulfan on AP-1 DNA-binding activity, electrophoretic mobility-shift assays were performed. Specific binding to the AP-1 containing oligonucleotide was detected, however, endosulfan treatment did not significantly affect the level of AP-1 binding. In summary, these results support a model where endosulfan induces intracellular oxidative stress to increase the JNK/SAPK activity. Activated JNK/SAPK in turn increases phosphorylation of c-JUN, which ultimately induce increases the level of transcription of genes encoding phase II detoxifying enzymes.
Key words: MAPK signaling pathway, Endosulfan, intracellular oxidative stress, HepG2 cells
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