title: Effects of organochlorine insecticides on MAP kinase pathways in human HaCaT keratinocytes: key role of reactive oxygen species.
abstract: Organochlorine pesticides (OCs) are reported as potential carcinogens in humans. The aim of this study was to investigate the effects of four OCs (dieldrin, endosulfan, heptachlor, and lindane) on mitogen-activated protein kinase (MAPK) cascades and more specifically to identify the mechanism underlying OC-induced ERK1/2 activation. Organochlorine pesticides increased phosphorylated Raf, MEK1/2, ERK1/2, and c-Jun in human HaCaT cells, but they had no effect on p38 MAPK activation. Moreover, blockade of Raf, MEK1/2, or PKC activation with geldanamycin, U0126, or calphostin C inhibited ERK1/2 phosphorylation, demonstrating a PKC-Raf-MEK1/2 pathway. We also showed that these insecticides induced the production of reactive oxygen species (ROS). Pre-treatment with the antioxidant molecule N-acetyl cysteine sharply decreased the level of phospho-ERK1/2 and had no effect on Raf and MEK1/2 activation, suggesting a Raf-independent mechanism. This study indicates that OCs strongly activate the ERK1/2 pathway, and it identifies a critical role of ROS in OC-induced ERK activation, probably by stabilizing its phosphorylation.
authors.affiliation: Laboratoire de Toxicologie Cellulaire et Moléculaire, Centre de Recherche INRA, 400 route des Chappes, 06903 Sophia-Antipolis, France. ledirac@antibes.inra.fr
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ledirac
authors.forename: Sebastien
authors.initials: S
authors.lastname: Antherieu
authors.forename: Anne Dupuy
authors.initials: AD
authors.lastname: d'Uby
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Caron
authors.forename: Roger
authors.initials: R
authors.lastname: Rahmani
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D007306:Insecticides / Q000633:toxicity*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D005452:Fluoresceins; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides; D017382:Reactive Oxygen Species; C029569:diacetyldichlorofluorescein; D017346:Protein Serine-Threonine Kinases