title: Fipronil is a powerful uncoupler of oxidative phosphorylation that triggers apoptosis in human neuronal cell line SHSY5Y.
abstract: Fipronil is a phenylpyrazole insecticide known to elicit neurotoxicity via an interaction with ionotropic receptors, namely GABA and glutamate receptors. Recently, we showed that fipronil and other phenylpyrazole compounds trigger cell death in Caco-2 cells. In this study, we investigated the mode of action and the type of cell death induced by fipronil in SH-SY5Y human neuroblastoma cells. Flow cytometric and western blot analyses demonstrated that fipronil induces cellular events belonging to the apoptosis process, such as mitochondrial potential collapse, cytochrome c release, caspase-3 activation, nuclear condensation and phosphatidylserine externalization. In addition, fipronil induces a rapid ATP depletion with concomitant activation of anaerobic glycolysis. This cellular response is characteristic of mitochondrial injury associated with a defect of the respiration process. Therefore, we also investigated the effect of fipronil on the oxygen consumption in isolated mitochondria. Interestingly, we show for the first time that fipronil is a strong uncoupler of oxidative phosphorylation at relative low concentrations. Thus in this study, we report a new mode of action by which the insecticide fipronil could triggers apoptosis.
authors.affiliation: INRA, Laboratoire de toxicologie environnementale, UMR 406, Abeille et environnement, 84914 Avignon Cedex 9, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Vidau
authors.forename: Rosa A
authors.initials: RA
authors.lastname: González-Polo
authors.forename: Mireia
authors.initials: M
authors.lastname: Niso-Santano
authors.forename: Rubén
authors.initials: R
authors.lastname: Gómez-Sánchez
authors.forename: José M
authors.initials: JM
authors.lastname: Bravo-San Pedro
authors.forename: Elisa
authors.initials: E
authors.lastname: Pizarro-Estrella
authors.forename: Rafael
authors.initials: R
authors.lastname: Blasco
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Brunet
authors.forename: Luc P
authors.initials: LP
authors.lastname: Belzunces
authors.forename: José M
authors.initials: JM
authors.lastname: Fuentes
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010718:Phosphatidylserines / Q000378:metabolism; D011720:Pyrazoles / Q000633:toxicity*; D013997:Time Factors; D014475:Uncoupling Agents / Q000633:toxicity*
chemical_list: D007306:Insecticides; D010718:Phosphatidylserines; D011720:Pyrazoles; D014475:Uncoupling Agents; D000255:Adenosine Triphosphate; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; C082360:fipronil