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

in Toxicological Sciences (2008), 102(1), 33-41

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 ... [more ▼]

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. [less ▲]

Assessment and mechanism of variations in pubertal timing in internationally adopted children: a developmental hypothesis

in European Journal of Endocrinology (2006), 155(Suppl. 1), 17-25

During the past decades, children migrating for international adoption have increased in number, creating an original condition of dramatic environmental change during development. In several countries ... [more ▼]

During the past decades, children migrating for international adoption have increased in number, creating an original condition of dramatic environmental change during development. In several countries, cohorts of these subjects have been shown to experience a global advancement in age at the onset of puberty, and sexual precocity is seen more frequently than in other conditions. Such early or precocious development has been assessed in relatively small cohorts or individual patients using well-defined physical indicators in comparison with updated references in the foster country. Family and adolescent evaluation of pubertal timing could allow for the study of large series of internationally adopted subjects. Also, this type of assessment integrates the physical changes of puberty with the adolescent changes in psychological and social functioning. The pathophysiological mechanisms leading to advancement of puberty in migrating children are still unclear and possibly involve several factors. In the present paper, we hypothesize that the sexual precocity in children migrating for international adoption could represent a developmentally programmed disorder resulting from cumulative anomalies in early remodeling of the central nervous system by communicational, social, nutritional, and hormonal inputs. There is some evidence that the deviations in those inputs can result in altered brain structure, particularly in the limbic system. We discuss the possible association with further disorders of developmental functions, such as cognitive, psychosocial, and sexual maturation. Along this hypothesis, some forms of idiopathic sexual precocity could result from dysfunction of one or several of the environmental programming factors, while other forms may involve predominantly genetic or familial factors. [less ▲]

Early onset of puberty: Tracking genetic and environmental factors

in Hormone Research (2005), 64(Suppl. 2), 41-47

Under physiological conditions, factors affecting the genetic control of hypothalamic functions are predominant in determining the individual variations in timing of pubertal onset. In pathological ... [more ▼]

Under physiological conditions, factors affecting the genetic control of hypothalamic functions are predominant in determining the individual variations in timing of pubertal onset. In pathological conditions, however, these variations can involve different genetic susceptibility and the interaction of environmental factors. The high incidence of precocious puberty in foreign children migrating to Belgium and the detection in their plasma of a long-lasting 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (DDT) residue suggest the potential role of environmental endocrine disrupting chemicals in the early onset of puberty. This hypothesis was confirmed by experimental data showing thattemporary exposure of immature female rats to DDT in vivo results in early onset of puberty. We compared the gene expression profile of hypothalamic hamartoma associated or not with precocious puberty in order to identify gene networks responsible for both hamartoma-dependent sexual precocity and the onset of normal human puberty. In conclusion, pathological variations in the timing of puberty may provide unique information about the interactions of either environmental conditions or genetic susceptibility with the hypothalamic mechanism controlling the onset of sexual maturation, as shown by examples of precocious puberty following exposure to endocrine disrupters or due to hypothalamic hamartoma. Copyright (c) 2005 S. Karger AG, Basel. [less ▲]