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ToxSci Advance Access published online on May 11, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi192
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Published by Oxford University Press 2005.
Received March 7, 2005
Accepted April 28, 2005

Systems Toxicology

Effects of organochlorine insecticides on MAP kinase pathways in human HaCaT keratinocytes : Key role of reactive oxygen species

Nathalie Ledirac 1* {ddagger}, Sebastien Antherieu 1 {ddagger}, Anne Dupuy d'Uby 1, Jean-Claude Caron 2, and Roger Rahmani 1

1 Laboratoire de Toxicologie Cellulaire et Moléculaire, Centre de Recherche INRA, 400 route des Chappes, 06903 Sophia-Antipolis, France
2 Galderma R&D, les Templiers, 2400 routes des Colles, 06410 Biot, France

* To whom correspondence should be addressed.
Nathalie Ledirac, E-mail: ledirac{at}antibes.inra.fr


  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 MAPK cascades and more specifically to identify the mechanism underlying OCs-induced ERK1/2 activation. OCs increased phosphorylated Raf, MEK1/2, ERK1/2 and c-Jun in human HaCaT cells, but 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 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 Rafindependent mechanism. This study indicates that OCs strongly activate the ERK1/2 pathway, and identifies a critical role of ROS in OCs-induced ERK activation probably by stabilizing its phosphorylation.

Keywords: ERK1/2; Keratinocytes; Mitogen-activated protein kinases; Organochlorines; Reactive oxygen species; Signal transduction.

{ddagger}These authors have equally contributed to the work.


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