Nitrofen induces a redox-dependent apoptosis associated with increased p38 activity in P19 teratocarcinoma cells.

Abstract

Nitrofen is a diphenyl ether herbicide that produces a spectrum of fetal abnormalities in rodents. To characterize the molecular mechanisms of nitrofen-mediated birth defects at the cellular level, we explored its effects on undifferentiated P19 teratocarcinoma cells. Nitrofen induces a time-dependent cell death of P19 cells that is associated with increases in TUNEL-positivity and caspase-3 cleavage suggesting that nitrofen induces P19 cell apoptosis. In addition, the increase in TUNEL-positive cells was inhibited with zVAD-fmk, suggesting that nitrofen induces a caspase-dependent apoptosis. Nitrofen treatment was associated with increased p38 MAP kinase activity, though pretreatment of cells with multiple p38 inhibitors did not affect nitrofen-mediated caspase-3 cleavage, suggesting caspase-3 cleavage is p38-independent. Nitrofen induced a dose-dependent increase in reactive oxygen species (ROS), which was accompanied by a decrease in the ratio of reduced/oxidized glutathione, indicating that nitrofen alters the cellular redox state of these cells. Furthermore, pretreatment of cells with N-acetyl cysteine gave a dose- and time-dependent reduction of caspase-3 cleavage, supporting the observations that caspase-3 cleavage is cell-redox-dependent. Therefore, nitrofen induces P19 cell apoptosis that is cell-redox-dependent and is associated with increases in p38 activity and ROS and may play a role in nitrofen-mediated birth defects.

• Authors: D E Kling, J T Aidlen, J C Fisher, T B Kinane, P K Donahoe, J J Schnitzer
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 19 Issue 1 Pg. 1-10 (Feb 2005) ISSN: 0887-2333 [Print] England
• PMID: 15582350 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Herbicides
• Phenyl Ethers
• p38 Mitogen-Activated Protein Kinases
• nitrofen

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor (drug effects, enzymology, pathology)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Herbicides (toxicity)
• In Situ Nick-End Labeling
• Mice
• Oxidation-Reduction
• Phenyl Ethers (toxicity)
• Teratocarcinoma (drug therapy, enzymology, pathology)
• p38 Mitogen-Activated Protein Kinases (metabolism)