Mechanisms of interaction of endocrine-disrupting chemicals with glutamate-evoked secretion of gonadotropin-releasing hormone.
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.
Rasier
Grégory
G
Developmental Neuroendocrinology Unit, Centre for Cellular and Molecular Neurobiology, University of Liège, University Hospital, Belgium.
Parent
Anne-Simone
AS
Gérard
Arlette
A
Denooz
Raphaël
R
Lebrethon
Marie-Christine
MC
Charlier
Corinne
C
Bourguignon
Jean-Pierre
JP
D000818:Animals; D001559:Benzhydryl Compounds; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003634:DDT / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D004958:Estradiol / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism; D007279:Injections, Subcutaneous; D008731:Methoxychlor / Q000633:toxicity; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010636:Phenols / Q000633:toxicity; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D012741:Sexual Maturation / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D046509:Tissue Culture Techniques; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D017868:Cyclic AMP-Dependent Protein Kinases; D003634:DDT; D052244:Endocrine Disruptors; D004958:Estradiol; D004965:Estrogen Antagonists; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D007987:Gonadotropin-Releasing Hormone; D008731:Methoxychlor; D020928:Mitogen-Activated Protein Kinases; D010636:Phenols; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D018091:Receptors, AMPA; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; C006780:bisphenol A; D000098826:Bisphenol A Compounds