Effects of organochlorine insecticides on MAP kinase pathways in human HaCaT keratinocytes: key role of reactive oxygen species.
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.
Ledirac
Nathalie
N
Laboratoire de Toxicologie Cellulaire et Moléculaire, Centre de Recherche INRA, 400 route des Chappes, 06903 Sophia-Antipolis, France. ledirac@antibes.inra.fr
Antherieu
Sebastien
S
d'Uby
Anne Dupuy
AD
Caron
Jean-Claude
JC
Rahmani
Roger
R
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*
D005452:Fluoresceins; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides; D017382:Reactive Oxygen Species; C029569:diacetyldichlorofluorescein; D017346:Protein Serine-Threonine Kinases