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

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.

Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents

“…Using DDT during early postnatal life or after weaning, the dose appears critical for occurrence of early VO (Rasier et al, 2007;Heinrichs et al, 1971). Some of the mechanistic data that we have obtained in the hypothalamus after early postnatal exposure to DDT (Rasier et al, 2008(Rasier et al, ,2007 are illustrated in Fig. 9.…”

“…So, with caution, we have attempted to delineate (Tables 5-7) whether given EDCs would influence pubertal timing in humans differently depending on the presumable period of exposure. As far as the insecticide DDT and its derivative DDE, the interpretation is complex since the former has prominently estrogenic properties and the latter is considered to be anti-androgenic (Rasier et al, 2008). Moreover, DDE is present as a minor constituent in commercial DDT preparations and arises as well from degradation of DDT in the body.…”

“…Further studies have indicated that such effects involve the estrogen receptor, the orphan dioxin (AhR, aryhydrocarbon) receptor and a subtype of glutamate receptor (Rasier et al, 2008). M) or a Aryl hydrocarbon receptor antagonist (α-naphtoflavone, 10 -7 M).…”

Early homeostatic disturbances of human growth and maturation by endocrine disrupters

“…On the basis of increased serum levels of DDE, a derivative of the estrogenic insecticide DDT found among migrating children, we hypothesized that early exposure to this EDC and subsequent withdrawal due to migration could account for a neuroendocrine pathogenetic mechanism of secondary central precocious puberty [31,32]. This hypothesis was substantiated in a rat model [7,34]. The mechanistic interpretation is that, during exposure to DDT, estrogenic effects account for both peripheral and central (neuroendocrine) stimulation.…”

“…Consistent with this concept is the observation that premature breast development can occur after exposure to phthalates, which are considered to act primarily as androgen antagonists [6]. Moreover, an estrogenic compound such as DDT can generate the antiandrogenic sub-product dichlorodiphenylchloroethene (DDE), which can also indirectly reflect previous exposure to DDT, further complicating the elucidation of estrogenic versus antiandrogenic effects [7]. Since both the reproductive and energy balance systems are regulated by feedback loops between peripheral tissues on the one hand and pituitary gland, hypothalamus and CNS on the other hand, EDCs can have an effect at any of those sites directly or secondarily through changes in hypothalamic-pituitary messengers or altered peripheral feedback.…”