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Activation of retinoic acid receptor-dependent transcription by organochlorine pesticides
Activation of retinoic acid receptor-dependent transcription by organochlorine pesticides
- 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.
- Subjects :
- Transcriptional Activation
Insecticides
medicine.drug_class
Receptors, Retinoic Acid
[SDV]Life Sciences [q-bio]
Retinoic acid
Chlordane
010501 environmental sciences
Biology
Retinoid X receptor
Naphthalenes
Toxicology
01 natural sciences
Benzoates
03 medical and health sciences
chemistry.chemical_compound
Transactivation
Retinoids
Cytochrome P-450 Enzyme System
medicine
Hydrocarbons, Chlorinated
Animals
Humans
Aldrin
RETINOIC ACID RECEPTOR
Retinoid
ComputingMilieux_MISCELLANEOUS
030304 developmental biology
0105 earth and related environmental sciences
ORGANOCHLORINE PESTICIDES
Pharmacology
0303 health sciences
CYTOCHROME P450RAI1
Retinoic Acid 4-Hydroxylase
Retinoic acid receptor
Biochemistry
chemistry
Enzyme Induction
COS Cells
Estrogen receptor alpha
HeLa Cells
Subjects
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⟩