title: Enantiomer-specific, bifenthrin-induced apoptosis mediated by MAPK signalling pathway in Hep G2 cells.
abstract: 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.
authors.affiliation: Research Centre of Environmental Science, College of Biology and Environment, Zhejiang University of Technology, Hangzhou 310032, China.
authors.forename: Huigang
authors.initials: H
authors.lastname: Liu
authors.forename: Lihong
authors.initials: L
authors.lastname: Xu
authors.forename: Meirong
authors.initials: M
authors.lastname: Zhao
authors.forename: Weiping
authors.initials: W
authors.lastname: Liu
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000737:chemistry / Q000633:toxicity*; D007536:Isomerism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011722:Pyrethrins / Q000737:chemistry / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007306:Insecticides; D047428:Protein Kinase Inhibitors; D011722:Pyrethrins; D017382:Reactive Oxygen Species; C099952:bifenthrin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases