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ToxSci Advance Access published online on November 20, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm285
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mechanisms of Interaction of Endocrine Disrupting Chemicals with Glutamate-Evoked Secretion of Gonadotropin-Releasing Hormone

Grégory Rasier1, Anne-Simone Parent1, Arlette Gérard1, Raphaël Denooz2, Marie-Christine Lebrethon1, Corinne Charlier2 and Jean-Pierre Bourguignon1

1 Developmental Neuroendocrinology Unit, Centre for Cellular and Molecular Neurobiology 2 Clinical, Forensic and Environmental Toxicology Laboratory, University of Liège, University Hospital, B-4000 Liège (Sart-Tilman), Belgium

Corresponding author: Jean-Pierre Bourguignon, M.D., Ph.D., Division of Paediatric Endocrinology and Adolescent Medicine, University Hospital, B-4000 Liège (Sart-Tilman), Belgium. E-mail: jpbourguignon{at}ulg.ac.be, Phone: + 32 4 366 72 47, Fax: + 32 4 366 72 46

Received August 17, 2007; revision received October 14, 2007; accepted October 15, 2007


  Abstract

In previous studies, we detected a dichlorodiphenyltrichloroethane (DDT) derivative in the serum of children with sexual precocity after migration from developing countries. Recently, we reported that DDT stimulated pulsatile gonadotropin-releasing hormone (GnRH) secretion and sexual maturation in the female rat. The aim of this study was to delineate the mechanisms of interaction of endocrine disrupting chemicals including DDT with GnRH secretion evoked by glutamate in vitro. Using hypothalamic explants obtained from 15-day-old female rats, estradiol (E2) and DDT caused a concentration-related increase in glutamate-evoked GnRH release while p,p'-dichlorodiphenyldichloroethene and methoxychlor had no effect. The effective DDT concentrations in vitro were consistent with the serum concentrations measured in vivo 5 days after exposure of immature rats to 10 mg/kg.day of o,p'-DDT. Bisphenol A induced some stimulatory effect whereas no change was observed with 4-nonylphenol. The o,p'-DDT effects in vitro were prevented partially by a selective antagonist of the {alpha}-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of glutamate receptors. A complete prevention of o,p'-DDT effects was caused by an estrogen receptor (ER) antagonist as well as an aryl hydrocarbon receptor (AHR) antagonist and inhibitors of protein kinases A and C, and mitogen-activated kinases. While an intermittent incubation with E2 caused no change in amplification of the glutamate-evoked GnRH release for 4 h, continuous incubation with E2 or o,p'-DDT caused an increase of this amplification after 3.5 h of incubation. In summary, DDT amplifies the glutamate-evoked GnRH secretion in vitro through rapid and slow effects involving ER-, AHR- and AMPA receptor-mediation.

Key Words: Gonadotropin-releasing hormone; Endocrine disrupting chemicals; Glutamate receptors; Estrogen receptors; Aryl hydrocarbon receptor.


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