title: Phenylpyrazole insecticides induce cytotoxicity by altering mechanisms involved in cellular energy supply in the human epithelial cell model Caco-2.
abstract: Phenylpyrazoles are relatively new insecticides designed to manage problematic insect resistance and public health hazards encountered with older pesticide families. In vitro cytotoxicity induced by the phenylpyrazole insecticides, Ethiprol and Fipronil, and Fipronil metabolites, sulfone and sulfide, was studied in Caco-2 cells. This cellular model was chosen because it made possible to mimic the primary site of oral exposure to xenobiotics, the intestinal epithelium. Assessment of the barrier function of Caco-2 epithelium was assessed by TEER measurement and showed a major loss of barrier integrity after exposure to Fipronil and its metabolites, but not to Ethiprol. The disruption of the epithelial barrier was attributed to severe ATP depletion independent of cell viability, as revealed by LDH release. The origin of energetic metabolism failure was investigated and revealed a transient enhancement of tetrazolium salt reduction and an increase in lactate production by Caco-2 cells, suggesting an increase in glucose metabolism by pesticides. Cellular symptoms observed in these experiments lead us to hypothesize that phenylpyrazole insecticides interacted with mitochondria.
authors.affiliation: INRA, UMR 406 A&E, Laboratoire de Toxicologie Environnementale, Site Agroparc, F-84000 Avignon, Cedex 9, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Vidau
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Brunet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Badiou
authors.forename: Luc P
authors.initials: LP
authors.lastname: Belzunces
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D004734:Energy Metabolism / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000096:biosynthesis; D008928:Mitochondria / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: D007306:Insecticides; D011720:Pyrazoles; D019344:Lactic Acid; C472185:ethiprole; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; C082360:fipronil