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ToxSci Advance Access originally published online on November 20, 2007
Toxicological Sciences 2008 102(1):33-41; 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 Rasier*, Anne-Simone Parent*, Arlette Gérard*, Raphaël Denooz{dagger}, Marie-Christine Lebrethon*, Corinne Charlier{dagger} and Jean-Pierre Bourguignon*,1

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

1 To whom correspondence should be addressed at Division of Paediatric Endocrinology and Adolescent Medicine, University Hospital, B-4000 Liège (Sart-Tilman), Belgium. Fax: +32-4-366-72-46. E-mail: jpbourguignon{at}ulg.ac.be.

Received August 17, 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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