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ToxSci Advance Access originally published online on May 11, 2005
Toxicological Sciences 2005 86(2):444-452; doi:10.1093/toxsci/kfi192
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Effects of Organochlorine Insecticides on MAP Kinase Pathways in Human HaCaT Keratinocytes: Key Role of Reactive Oxygen Species

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

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

Received March 7, 2005; accepted April 28, 2005

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.

Key Words: ERK1/2; keratinocytes; mitogen-activated protein kinases; organochlorines; reactive oxygen species; signal transduction.


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