bifenthrin and Liver-Neoplasms

Enantioselectivity in toxicology, and health risk of chiral xenobiotics have become important topics at the forefront of chemistry and toxicology research. Our previous results showed that cis-bifenthrin (cis-BF) induced cytotoxicity and genotoxicity in human amnion epithelial (FL) cells, in an enantioselective manner. However, the exact molecular mechanisms of synthetic pyrethroid-induced, enantioselective apoptosis and cytotoxicity remain unclear. In this study, enantiomers of the synthetic pyrethroid-based insecticide, cis-BF, were separated on selected chiral columns by HPLC. Enantioselectivity in cytotoxicity and apoptosis, mediated by the mitogen-activated protein kinase (MAPK) signalling pathway, were evaluated in the human hepatocellular liver carcinoma (Hep G2) cell line. Exposure to 1S-cis-BF resulted in increased levels of phosphorylated JNK (Jun-N-terminal Kinases)/MAPKs, while exposure to 1R-cis-BF did not affect phosphorylated JNK levels. Pre-treatment with the JNK inhibitor SP600125, blocked 1S-cis-BF-induced cytotoxicity and apoptosis. In addition, 1S-cis-BF enhanced the production of ROS, while pre-treatment with the antioxidant agent MnTBAP resulted in decreased phosphorylation of JNK. To the best of our knowledge, this is the first report demonstrating that cis-BF-induced apoptosis might occur, at least in part, through the enantioselective activation of JNK/MAPK signalling pathway in Hep G2 cells. The results suggest that enantioselectivity should be considered when evaluating eco-toxicological effects and health risks of chiral contaminants, and could also improve the understanding of molecular mechanisms responsible for chiral chemical-induced cytotoxicity and apoptosis.

Topics: Antioxidants; Apoptosis; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Humans; Insecticides; Isomerism; JNK Mitogen-Activated Protein Kinases; Liver Neoplasms; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase Inhibitors; Pyrethrins; Reactive Oxygen Species; Time Factors