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Activation of retinoic acid receptor-dependent transcription by organochlorine pesticides

Activation of retinoic acid receptor-dependent transcription by organochlorine pesticides

Authors :
Roger Rahmani
Serge Michel
Géraldine Lemaire
Patrick Balaguer
Réponse des Organismes aux Stress Environnementaux (ROSE)
Institut National de la Recherche Agronomique (INRA)-Université Nice Sophia Antipolis (... - 2019) (UNS)
COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)
Endocrinologie moléculaire et cellulaire des cancers
Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Galderma International S.A.S. [Paris, France]
Source :
Toxicology and Applied Pharmacology, Toxicology and Applied Pharmacology, Elsevier, 2005, 202 (1), pp.38-49. ⟨10.1016/j.taap.2004.06.004⟩
Publication Year :
2004

Abstract

Five organochlorine pesticides, namely, chlordane, dieldrin, aldrin, endrin, and endosulfan, activate human retinoic acid receptor (RAR)-mediated gene transcription via a retinoic acid response element (RARE). Transactivation studies were performed with stable RARalpha, beta, or gamma reporter cell lines in which the RAR DNA-binding domain (DBD) was replaced by that of estrogen receptor alpha (ERalpha)? Five of the organochlorine pesticides tested activated RARbeta and RARgamma but not RARalpha; their half-maximal luciferase activity (EC(50)) was determined. Furthermore, that activity was RAR-specific and organochlorine pesticides did not activate the retinoid X receptor (RXR) pathway. However, competitive binding experiments with [(3)H]-CD367, a pan-RAR agonist, showed that only chlordane could bind RARbeta and RARgamma, albeit with low affinity. In addition, organochlorine pesticides strongly induce cytochrome P450RAI1 (P450RAI1), a key factor of retinoic acid level regulation in many tissues and whose expression and activity are strongly induced by retinoic acid. This study shows that organochlorine pesticides can activate two RAR homologues, with low-binding affinity. Although the agonistic potential of organochlorine pesticides is lower than that of (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl] benzoic acid (TTNPB), they are able to induce RAR-mediated gene transcription as P450RAI1 and may disrupt the retinoid signaling pathway. Because these chemicals are extremely persistent and tend to accumulate in biological tissues, these results support the hypothesis that the increase in teratogenicity observed in some developing countries could be due to prolonged exposure to organochlorine pesticides ubiquitously present in the environment.

Details

ISSN :
0041008X and 10960333
Volume :
202
Issue :
1
Database :
OpenAIRE
Journal :
Toxicology and applied pharmacology
Accession number :
edsair.doi.dedup.....11b0f02c0f0205fdc3b3a702e6976231
Full Text :
https://doi.org/10.1016/j.taap.2004.06.004⟩