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See detailEarly developmental actions of endocrine disruptors on the hypothalamus, hippocampus, and cerebral cortex.
Parent, Anne-Simone ULg; Naveau, Elise; GERARD, Arlette ULg et al

in Journal of Toxicology and Environmental Health. Part B, Critical Reviews (2011), 14(5-7), 328-45

Sex steroids and thyroid hormones play a key role in the development of the central nervous system. The critical role of these hormonal systems may explain the sensitivity of the hypothalamus, the ... [more ▼]

Sex steroids and thyroid hormones play a key role in the development of the central nervous system. The critical role of these hormonal systems may explain the sensitivity of the hypothalamus, the cerebral cortex, and the hippocampus to endocrine-disrupting chemicals (EDC). This review examines the evidence for endocrine disruption of glial-neuronal functions in the hypothalamus, hippocampus, and cerebral cortex. Focus was placed on two well-studied EDC, the insecticide dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCB). DDT is involved in neuroendocrine disruption of the reproductive axis, whereas polychlorinated biphenyls (PCB) interact with both the thyroid hormone- and sex steroid-dependent systems and disturb the neuroendocrine control of reproduction and development of hippocampus and cortex. These results highlight the impact of EDC on the developing nervous system and the need for more research in this area. [less ▲]

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See detailNeuroendocrine disruption of pubertal timing and interactions between homeostasis
Bourguignon, Jean-Pierre ULg; rasier, Gregory; Lebrethon, Marie-Christine ULg et al

in Molecular & Cellular Endocrinology (2010), 324(1-2), 110-120

The involvement of environmental factors such as endocrine disrupting chemicals (EDCs) in the timing of onset of puberty is suggested by recent changes in age at onset of puberty and pattern of ... [more ▼]

The involvement of environmental factors such as endocrine disrupting chemicals (EDCs) in the timing of onset of puberty is suggested by recent changes in age at onset of puberty and pattern of distribution that are variable among countries, as well as new forms of sexual precocity after migration. However, the evidence of association between early or late pubertal timing and exposure to EDCs is weak in humans, possibly due to heterogeneity of effects likely involving mixtures and incapacity to assess fetal or neonatal exposure retrospectively. The neuroendocrine system which is crucial for physiological onset of puberty is targeted by EDCs. These compounds also act directly in the gonads and peripheral sex-steroid sensitive tissues. Feedbacks add to the complexity of regulation so that changes in pubertal timing caused by EDCs can involve both central and peripheral mechanisms. In experimental conditions, several neuroendocrine endpoints are affected by EDCs though only few studies including from our laboratory aimed at EDC involvement in the pathophysiology of early sexual maturation. Recent observations support the concept that EDC cause disturbed energy balance and account for the obesity epidemic. Several aspects are linking this system and the reproductive axis: coexisting neuroendocrine and peripheral effects, dependency on fetal/neonatal programming and the many factors cross-linking the two systems, for instance leptin, adiponectin, Agouti Related Peptide (AgRP). This opens perspectives for future research and, hopefully, measures preventing the disturbances of homeostasis caused by EDCs. [less ▲]

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See detailOxytocin Facilitates Female Sexual Maturation through a Glia-to-Neuron Signaling Pathway
Parent, Anne-Simone ULg; Rasier, Grégory ULg; Matagne, V. et al

in Endocrinology (2008), 149(3), 1358-65

It has been earlier proposed that oxytocin could play a facilitatory role in the preovulatory LH surge in both rats and humans. We here provide evidence that oxytocin also facilitates sexual maturation in ... [more ▼]

It has been earlier proposed that oxytocin could play a facilitatory role in the preovulatory LH surge in both rats and humans. We here provide evidence that oxytocin also facilitates sexual maturation in female rats. The administration of an oxytocin antagonist for 6 d to immature female rats decreased GnRH pulse frequency ex vivo and delayed the age at vaginal opening and first estrus. The in vitro reduction in GnRH pulse frequency required chronic blockade of oxytocin receptors, because it was not acutely observed after a single injection of the antagonist. Hypothalamic explants exposed to the antagonist in vitro showed a reduced GnRH pulse frequency and failed to respond to oxytocin with GnRH release. Prostaglandin E(2) (PGE(2)) mimicked the stimulatory effect of oxytocin on GnRH pulse frequency, and inhibition of PG synthesis blocked the effect of oxytocin, suggesting that oxytocin accelerates pulsatile GnRH release via PGE(2). The source of PGE(2) appears to be astrocytes, because oxytocin stimulates PGE(2) release from cultured hypothalamic astrocytes. Moreover, astrocytes express oxytocin receptors, whereas GnRH neurons do not. These results suggest that oxytocin facilitates female sexual development and that this effect is mediated by a mechanism involving glial production of PGE(2). [less ▲]

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See detailMechanisms of Interaction of Endocrine-Disrupting Chemicals with Glutamate-Evoked Secretion of Gonadotropin-Releasing Hormone
Rasier, Gregory; Parent, Anne-Simone ULg; Gerard, Arlette ULg et al

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 ▲]

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See detailEarly maturation of gonadotropin-releasing hormone secretion and sexual precocity after exposure of infant female rats to estradiol or dichlorodiphenyltrichloroethane
Rasier, Gregory; Parent, Anne-Simone ULg; Gerard, Arlette ULg et al

in Biology of Reproduction (2007), 77(4), 734-742

An increase in the frequency of pulsatile gonadotropin-releasing hormone (GnRH) secretion in vitro and a reduction in LH response to GnRH in vivo characterize hypothalamic-pituitary maturation before ... [more ▼]

An increase in the frequency of pulsatile gonadotropin-releasing hormone (GnRH) secretion in vitro and a reduction in LH response to GnRH in vivo characterize hypothalamic-pituitary maturation before puberty in the female rat. In girls migrating for international adoption, sexual precocity is frequent and could implicate former exposure to the insecticide dichlorodiphenyltrichloroethane (DDT), since a long-lasting DDT derivative has been detected in the serum of such children. We aimed at studying the effects of early transient exposure to estradiol (E 2) or DDT in vitro and in vivo in the infantile female rat. Using a static incubation system of hypothalamic explants from 15-day-old female rats, a concentration- and time-dependent reduction in GnRH interpulse interval (IPI) was seen during incubation with E 2 and DDT isomers. These effects were prevented by antagonists of alpha-amino-3-hydroxy-5-methyl-isoxazole-4 propionic acid (AMPA)/kainate receptors and estrogen receptor. Also, o,p '-DDT effects were prevented by an antagonist of the aryl hydrocarbon orphan dioxin receptor (AHR). After subcutaneous injections of E, or o,p '-DDT between Postnatal Days (PNDs) 6 and 10, a decreased GnRH IPI was observed on PND 15 as an ex vivo effect. After DDT administration, serum LH levels in response to GnRH were not different from controls on PIND 15, whereas they tended to be lower on PND 22. Subsequently, early vaginal opening (VO) and first estrus were observed together with a premature age-related decrease in LH response to GnRH. After prolonged exposure to E 2 between PNDs 6 and 40, VO occurred at an earlier age, but first estrus was delayed. We conclude that a transient exposure to E 2 or o,p '-DDT in early postnatal life is followed by early maturation of pulsatile GnRH secretion and, subsequently, early developmental reduction of LH response to GnRH that are possible mechanisms of the subsequent sexual precocity. The early maturation of pulsatile GnRH secretion could involve effects mediated through estrogen receptor and/or AHR as well as AMPA/kainate subtype of glutamate receptors. [less ▲]

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See detailEffects of in vivo and in vitro administration of ghrelin, leptin and neuropeptide mediators on pulsatile gonadotrophin-releasing hormone secretion from male rat hypothalamus before and after puberty
Lebrethon, Marie-Christine; Aganina, Anastasia; Fournier, Michael et al

in Journal of Neuroendocrinology (2007), 19(3), 181-188

The present study aimed to investigate the effects of leptin and ghrelin on pulsatile pulsatile gonadotrophin-releasing hormone (GnRH) secretion in vitro with emphasis on neuropeptide mediators and ... [more ▼]

The present study aimed to investigate the effects of leptin and ghrelin on pulsatile pulsatile gonadotrophin-releasing hormone (GnRH) secretion in vitro with emphasis on neuropeptide mediators and changes between prepuberty (15 days) and sexual maturity (50 days) in the male rat. When hypothalamic explants were studied 90 min after an intraperitoneal injection of leptin, ghrelin or agouti-related protein (AgRP) at 15 days, the GnRH interpulse interval (IPI) was significantly increased by ghrelin and AgRP and decreased by leptin. At 50 days, an increase in GnRH IPI was also caused by ghrelin and AgRP. When the peptides were directly incubated with the explants, the effects of leptin and AgRP in vitro were consistent with those seen after in vivo administration. By contrast, ghrelin resulted in a reduction of GnRH IPI and this was observed at 15 days only. To delineate the neuropeptide mediators of leptin and the effects of ghrelin in the hypothalamus, various hypothalamic neuropeptides and antagonists were used in vitro. At 15 days, the GnRH IPI was significantly decreased after incubation with cocaine and amphetamine-regulated transcript (CART), alpha-melanocyte-stimulating hormone, corticotrophin-releasing factor (CRF) and neuropeptide Y (NPY). The reduction of GnRH IPI caused by leptin was partially prevented by either an anti-CART antiserum or SHU 9119, a melanocortin MC3/MC4 receptor antagonist or a CRF receptor antagonist. The NPY-Y5 receptor antagonist did not influence the effects of leptin whereas that antagonist totally prevented the decrease in GnRH IPI caused by ghrelin. The ghrelin-induced reduction of GnRH IPI was partially prevented by SHU 9119. When used alone, SHU 9119 or a CRF-receptor antagonist resulted in increased GnRH IPI at 50 days while they had no effects at 15 days. The NPY-Y5 receptor antagonist resulted in increased GnRH IPI at 15 and 50 days. In conclusion, leptin and ghrelin show opposing effects on pulsatile GnRH secretion after administration in vivo whereas they both have stimulatory effects in vitro. Such effects involve consistently the anorectic peptides CART and CRF for leptin that are mainly active at 15 days. The melanocortigenic system appears to mediate the effects of both leptin and ghrelin. The effects of ghrelin also involve NPY receptors and operate effectively before and at sexual maturity. [less ▲]

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See detailFactors accounting for perinatal occurrence of pulsatile gonadotropin-releasing hormone secretion in vitro in rats
Parent, Anne-Simone ULg; Lebrethon, M. C.; Gerard, Arlette ULg et al

in Biology of Reproduction (2005), 72(1), 143-149

Our aim was to study the inhibitory and facilitatory factors possibly accounting for the undetectable activity of the GnRH pulse generator in late fetal life in vitro and its awakening in early postnatal ... [more ▼]

Our aim was to study the inhibitory and facilitatory factors possibly accounting for the undetectable activity of the GnRH pulse generator in late fetal life in vitro and its awakening in early postnatal life. Gamma aminobutyric acid (GABA(A)) receptor antagonism using SR 95 531 did not cause any secretory pulse in fetal explants, whereas a significant stimulation of GnRH pulse frequency was obtained at 5 and 15 days. GnRH secretory response to repeated N-methyl-D-aspartate (NMDA) stimulation showed progressive disappearance, indicating that the inhibitory autofeedback was operating. GnRH release caused by glutamine was respectively 9% and 20% of that evoked by glutamate in fetal and 5-day-old rats whereas both amino acids were equally active at 15 days. Explants obtained after cesarean section performed at onset of labor did not show any secretory pulse, while pulses could be observed with explants obtained 2 h after vaginal delivery. Incubation of fetal explants with oxytocin (10(-8) M) or prostaglandin E-2 (PGE(2)) (10(-6) M) resulted in occurrence of GnRH secretory pulses. A facilitatory effect of the oxytocin was shown to persist on Days 1, 5, and 15 and inhibitory effects of an oxytocin receptor antagonist provided some evidence of endogenous oxytocin involvement. We conclude that, in the fetal rat hypothalamus, GnRH inhibitory autofeedback and GABAergic inputs do not account for the absence of pulsatile GnRH secretion in vitro. A low rate of glutamate biosynthesis from glutamine is a possibly limiting factor. Oxytocin and PGE(2) can play a facilitatory role in the postpartal occurrence of pulsatile GnRH secretion. [less ▲]

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See detailEarly onset of puberty: Tracking genetic and environmental factors
Parent, Anne-Simone ULg; Rasier, Gregory; Gerard, Arlette ULg et al

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 ▲]

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See detailEstradiol stimulation of Pulsatile gonadotropin-releasing hormone secretion in vitro: Correlation with perinatal exposure to sex steroids and induction of sexual precocity in vivo
Matagne, V.; Rasier, G.; LEBRETHON, Marie-Christine ULg et al

in Endocrinology (2004), 145(6), 2775-2783

Our aim was to study the effect of estradiol (E2) on pulsatile GnRH secretion in vitro in relation to sex and development. When hypothalamic explants obtained from 5- and 15-d-old female rats were exposed ... [more ▼]

Our aim was to study the effect of estradiol (E2) on pulsatile GnRH secretion in vitro in relation to sex and development. When hypothalamic explants obtained from 5- and 15-d-old female rats were exposed to E2 (10(-7) m), a reduction of GnRH interpulse interval (IPI) occurred but not at 25 and 50 d of age. This effect was prevented by the estrogen receptor antagonist ICI 182.780 and the AMPA/kainate receptor antagonist DNQX but not by the AMPA and N-methyl-D-aspartate receptor antagonists SYM 2206 and MK-801. E2 did not affect GnRH IPI in hypothalamic explants obtained from male rats. Therefore, the possible relation between the female-specific effects of E2 in vitro and perinatal sexual differentiation was investigated. When using explants obtained from female rats masculinized through testosterone injection on postnatal d 1, E2 was no longer effective in vitro at 5 and 15 d. In addition, with explants obtained from male rats demasculinized through perinatal aromatase inhibitor treatment, E2 became capable of decreasing GnRH IPI in vitro at 15 d. To study the possible pathophysiological significance of early hypothalamic E2 effects, female rats received a single E2 injection on postnatal d 10. This resulted in reduced GnRH IPI in vitro on d 15 as well as advancement in age at vaginal opening and first estrus. In conclusion, E2 decreases the GnRH IPI in the immature female hypothalamus in vitro through a mechanism that depends on perinatal brain sexual differentiation and that could be involved in some forms of female precocious puberty. [less ▲]

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See detailLeptin Effects on Pulsatile Gonadotropin Releasing Hormone Secretion from the Adult Rat Hypothalamus and Interaction with Cocaine and Amphetamine Regulated Transcript Peptide and Neuropeptide Y
Parent, Anne-Simone ULg; Lebrethon, M. C.; Gerard, Arlette ULg et al

in Regulatory Peptides (2000), 92(1-3), 17-24

Leptin may act as a negative feedback signal to the hypothalamic control of appetite through suppression of neuropeptide Y (NPY) secretion and stimulation of cocaine and amphetamine regulated transcript ... [more ▼]

Leptin may act as a negative feedback signal to the hypothalamic control of appetite through suppression of neuropeptide Y (NPY) secretion and stimulation of cocaine and amphetamine regulated transcript (CART). We aimed at studying the effects of leptin, CART and NPY on the hypothalamic control of the pituitary-gonadal system. Pulsatile gonadotropin-releasing hormone (GnRH) secretion was studied in vitro using retrochiasmatic hypothalamic explants from adult rats. In the female, GnRH pulse amplitude was significantly increased by leptin (10(-7) M) and CART (10(-6) M) irrespective of the estrus cycle phase while no such effects were seen in the male. The GnRH interpulse interval was not affected in both sexes. Passive immunoneutralization against CART caused a reduction in GnRH pulse amplitude in the female. A slight but significant increase in GnRH pulse amplitude was caused by NPY (10(-7) M) in the female. However, GnRH pulse amplitude was not affected by a Y5-receptor antagonist (10(-6) M) while the interpulse interval was significantly increased as shown previously in the male. The increase in GnRH pulse amplitude caused by leptin was totally prevented by coincubation with an anti-CART antiserum whereas it was not affected by coincubation with the NPY Y5-receptor antagonist (10(-7) M). In conclusion, leptin and NPY show separate permissive effects on GnRH secretion in the adult rat hypothalamus. In both sexes, NPY is prominently involved in the control of the frequency of pulsatile GnRH secretion through the Y5 receptor subtype. Leptin causes a female-specific facilitatory effect on GnRH pulse amplitude which is mediated by CART and which occurs irrespective of the estrus cycle phase. [less ▲]

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See detailCocaine and Amphetamine-Regulated-Transcript Peptide Mediation of Leptin Stimulatory Effect on the Rat Gonadotropin-Releasing Hormone Pulse Generator in Vitro
Lebrethon, M. C.; Vandersmissen, E.; Gerard, Arlette ULg et al

in Journal of Neuroendocrinology (2000), 12(5), 383-5

Pulsatile gonadotropin-releasing hormone (GnRH) secretion was studied in vitro using explants of the retrochiasmatic hypothalamus from prepubertal male and female rats. Leptin caused a dose-dependent ... [more ▼]

Pulsatile gonadotropin-releasing hormone (GnRH) secretion was studied in vitro using explants of the retrochiasmatic hypothalamus from prepubertal male and female rats. Leptin caused a dose-dependent reduction of the GnRH interpulse interval in both sexes. We studied the effects of cocaine- and amphetamine-regulated transcript (CART) since this peptide was shown recently to mediate the anorectic effects of leptin in the hypothalamus. CART caused a reduction of the GnRH interpulse interval. This effect was prevented using an anti-CART antiserum which could partially overcome leptin stimulatory effects as well. Using hypothalamic explants from Zucker rats homozygous for the leptin receptor mutation ( fa/fa), GnRH pulse frequency was not affected by leptin, while a significant acceleration was caused by the CART-peptide. In conclusion, leptin involves the hypothalamic CART-peptide to stimulate the prepubertal GnRH pulse generator in vitro. [less ▲]

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See detailEndogenous Glutamate Involvement in Pulsatile Secretion of Gonadotropin-Releasing Hormone: Evidence from Effect of Glutamine and Developmental Changes
Bourguignon, Jean-Pierre ULg; Gerard, Arlette ULg; Alvarez Gonzalez, Maria-Luz ULg et al

in Endocrinology (1995), 136(3), 911-6

The secretion of GnRH can be stimulated by glutamate (GLU) and GLU agonists, whereas GLU receptor antagonists inhibit GnRH. Using 6-diazo-5-oxo-L-norleucine (DON), an inhibitor of glutaminase, we aimed to ... [more ▼]

The secretion of GnRH can be stimulated by glutamate (GLU) and GLU agonists, whereas GLU receptor antagonists inhibit GnRH. Using 6-diazo-5-oxo-L-norleucine (DON), an inhibitor of glutaminase, we aimed to study the involvement of endogenous GLU in GnRH secretion through the effects of impaired GLU biosynthesis from its precursor glutamine (GLN). GnRH secretion by hypothalamic explants of male rats, aged 15 and 50 days, was compared, because the frequency of spontaneous GnRH secretory pulses showed a 2-fold increase between those two ages. Using explants of 50-day-old rats, GLN elicited GnRH secretion in a similar dose-related manner as GLU. DON prevented GLN-evoked secretion of GnRH, whereas the effect of GLU was not altered. DON also markedly inhibited spontaneous pulsatile secretion of GnRH and the secretory response to veratridine, a Na+ channel opener. The inhibitory effect of DON on veratridine-evoked secretion of GnRH was directly related to the duration of exposure to DON and the frequency of GnRH secretory episodes. Using explants of 15-day-old rats, GLN could elicit GnRH release, although this response was lower than GLU-evoked secretion of GnRH. The DON concentrations required for inhibition of veratridine-evoked secretion of GnRH were lower at 15 days than at 50 days. These data indicate that 1) GLU biosynthesis from GLN is a prerequisite to the physiological mechanism of pulsatile GnRH secretion; and 2) inhibition of veratridine- or GLN-induced secretion of GnRH requires higher DON concentrations after the onset of puberty than before. This suggests that glutaminase, the enzyme controlling GLU biosynthesis from GLN, shows increased activity after the onset of puberty when the frequency of pulsatile GnRH secretion is increased as well. [less ▲]

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See detailGonadotropin Releasing Hormone Inhibitory Autofeedback by Subproducts Antagonist at N-Methyl-D-Aspartate Receptors: A Model of Autocrine Regulation of Peptide Secretion
Bourguignon, Jean-Pierre ULg; Alvarez Gonzalez, Maria-Luz ULg; Gerard, Arlette ULg et al

in Endocrinology (1994), 134(3), 1589-92

The secretion of Gonadotropin-releasing Hormone (GnRH) involves activation of N-methyl-D-aspartate (NMDA) receptors. Here, we show that pulsatile GnRH secretion from hypothalamic explants is suppressed by ... [more ▼]

The secretion of Gonadotropin-releasing Hormone (GnRH) involves activation of N-methyl-D-aspartate (NMDA) receptors. Here, we show that pulsatile GnRH secretion from hypothalamic explants is suppressed by 1-5GnRH, an endogenous breakdown product of GnRH, while 2-10GnRH has no effect. GnRH secretion evoked by NMDA is selectively inhibited by 1-5GnRH and this effect is similar to that of AP-5, a competitive antagonist at NMDA receptors. In addition, 1-5GnRH accounts for a dose-related inhibition of tritiated glutamate binding to hypothalamic membrane preparations. Using GnRH secretion as a model of NMDA-receptor controlled system, the effect of different peptides has been studied. Growth Hormone Releasing Factor (GRF), Insulin-like Growth Factor-I (IGF-I) and Proinsulin result in inhibition of GnRH secretion. Bioactive subproducts of those peptides (1-29GRF, 4-701GF-I and insulin) do not show any effect, suggesting that their classical receptors are not involved. In contrast, GnRH secretion is inhibited by other subproducts (1-37GRF, 1-31GF-I and C-peptide) all terminating in a glutamate residue. These subproducts selectively suppress the NMDA-evoked secretion of GnRH. Protease inhibitors prevent the inhibitory effects of IGF-I on GnRH secretion. This, breakdown products of different peptide hormones are possible endogenous antagonists at NMDA receptors. This effect could account for an autocrine or paracrine limitation of NMDA-receptor-mediated secretion of peptides. [less ▲]

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See detailControl of Pulsatile Secretion of Gonadotrophin Releasing Hormone from Hypothalamic Explants
Bourguignon, Jean-Pierre ULg; Gerard, Arlette ULg; Alvarez Gonzalez, Maria-Luz ULg et al

in Human Reproduction (1993), 8 Suppl 2(NULL), 18-22

We have studied the secretion of gonadotrophin releasing hormone (GnRH) from hypothalamic explants of male rats at different ages in an attempt to delineate the neuroendocrine mechanism of the onset of ... [more ▼]

We have studied the secretion of gonadotrophin releasing hormone (GnRH) from hypothalamic explants of male rats at different ages in an attempt to delineate the neuroendocrine mechanism of the onset of puberty. In this paper, we review some of our recent studies and we provide evidence of a dual control played by receptors to neuroexcitatory amino acids. We showed previously that isolated explants of rat hypothalamus could secrete GnRH in a pulsatile manner. The onset of puberty was characterized by a 2-fold increase in frequency of GnRH secretory pulses. This reduction of the interval between GnRH pulses involved an inhibitory autofeedback effect of GnRH on the pulse generator which was shut off following a secretory episode. This period of refractoriness was longer before puberty than after the onset of puberty. Activation of receptors to neuroexcitatory amino acids (N-methyl-D-aspartate; NMDA-type) was involved in the mechanism of pulsatile GnRH secretion. Striking developmental changes in NMDA-receptor-mediated GnRH secretion were demonstrated with a maximal activity around the time of the onset of puberty. Similar changes occurred in orchidectomized animals, indicating that this maturational process was gonad-independent. While evidence accumulated that NMDA receptors were involved in a stimulatory control of GnRH secretion, we found that NMDA receptors mediated an inhibitory effect on GnRH secretion. This inhibitory effect was very potent in the immature hypothalamus and it showed a marked reduction in potency before onset of puberty.(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]

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See detailAcute Suppression of Gonadotropin-Releasing Hormone Secretion by Insulin-Like Growth Factor I and Subproducts: An Age-Dependent Endocrine Effect
Bourguignon, Jean-Pierre ULg; Gerard, Arlette ULg; Alvarez Gonzalez, Maria-Luz ULg et al

in Neuroendocrinology (1993), 58(5), 525-30

Using rat hypothalamic explants, we showed previously that activation of N-methyl-D-aspartate (NMDA) receptors was involved in the mechanism of gonadotropin-releasing hormone (GnRH) secretion. (1-3 ... [more ▼]

Using rat hypothalamic explants, we showed previously that activation of N-methyl-D-aspartate (NMDA) receptors was involved in the mechanism of gonadotropin-releasing hormone (GnRH) secretion. (1-3)Insulin-like growth factor I (IGF-I), the N-terminal tripeptide of IGF-I, was suggested to be a possible antagonist at NMDA receptors. Here, we study the effects of IGF-I and its subproducts, (1-3)IGF-I and (4-70)IGF-I, either given in vivo as a single subcutaneous injection or used in vitro, on the secretion of GnRH by hypothalamic explants. At the three ages studied (15, 25 and 50 days), (4-70)IGF-I does not show any effect. At 50 days, the in vivo administration or the in vitro use of IGF-I results in a dose-related inhibition of the GnRH secretion induced by veratridine, a depolarizing agent. In addition, the spontaneous pulsatile secretion of GnRH in vitro is transiently suppressed after the in vivo administration of IGF-I. (1-3)IGF-I results in an inhibitory effect similar to that of IGF-I. At 25 days, IGF-I and (1-3)IGF-I show the same effects as at 50 days though higher concentrations are required. At 15 days, IGF-I does not show any effect whereas a potent inhibition of GnRH secretion is observed using (1-3)IGF-I either in vivo or in vitro. At all ages, the effects of (1-3)IGF-I parallel those of AP-5, a competitive antagonist at NMDA receptors.(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]

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See detailNeuroendocrine Mechanism of Onset of Puberty. Sequential Reduction in Activity of Inhibitory and Facilitatory N-Methyl-D-Aspartate Receptors
Bourguignon, Jean-Pierre ULg; Gerard, Arlette ULg; Alvarez Gonzalez, Maria-Luz ULg et al

in Journal of Clinical Investigation (1992), 90(5), 1736-44

In humans and in several animal species, puberty results from changes in pulsatile gonadotropin-releasing hormone (GnRH) secretion in the hypothalamus. In particular, the frequency of pulsatile GnRH ... [more ▼]

In humans and in several animal species, puberty results from changes in pulsatile gonadotropin-releasing hormone (GnRH) secretion in the hypothalamus. In particular, the frequency of pulsatile GnRH secretion increases at the onset of puberty, as can be shown by using hypothalamic explants of male rats of 15 and 25 d. Previous observations from us and others suggested that the initiation of puberty could involve a facilitatory effect of excitatory amino acids mediated through N-methyl-D-aspartate (NMDA) receptors. We found that GnRH secretion could be activated through NMDA receptors only around the time of onset of puberty (25 d). The aim of this study was to clarify why this activation did not occur earlier (at 15 d) and could no longer be observed by the end of puberty (at 50 d). We studied GnRH secretion in the presence of MK-801, a noncompetitive antagonist of NMDA receptors or AP-5, a competitive antagonist. We showed that, in the hypothalamus of immature male rats (15 d), a highly potent inhibitory control of pulsatile GnRH secretion in vitro was mediated through NMDA receptors. These data were confirmed in vivo because administration of the antagonist MK-801 (0.001 mg/kg) to immature male rats resulted in early pubertal development. Onset of puberty (25 d) was characterized by the disappearance of that NMDA receptor-mediated inhibition, thus unmasking a facilitatory effect also mediated through NMDA receptors. During puberty, there was a reduction in activity of this facilitatory control which was no longer opposed by its inhibitory counterpart. We conclude that a sequential reduction in activity of inhibitory and facilitatory NMDA receptors provides a developmental basis for the neuroendocrine mechanism of onset of puberty. [less ▲]

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See detailGonadal-Independent Developmental Changes in Activation of N-Methyl-D-Aspartate Receptors Involved in Gonadotropin-Releasing Hormone Secretion
Bourguignon, Jean-Pierre ULg; Gerard, Arlette ULg; Alvarez Gonzalez, Maria-Luz ULg et al

in Neuroendocrinology (1992), 55(6), 634-41

Using hypothalamic explants of male rats, we have shown that the N-methyl-D-aspartate (NMDA) receptors involved in a stimulatory control of gonadotropin-releasing hormone (GnRH) secretion were transiently ... [more ▼]

Using hypothalamic explants of male rats, we have shown that the N-methyl-D-aspartate (NMDA) receptors involved in a stimulatory control of gonadotropin-releasing hormone (GnRH) secretion were transiently activated at 25 days around the time of onset of puberty. This was evidenced by studying the dose-related inhibition of veratridine-induced GnRH secretion by MK-801, a use dependent antagonist of NMDA receptors. An increase in sensitivity of GnRH secretion to the inhibitory effect of MK-801 was used as a marker of increased activation of NMDA receptors involved in stimulation of GnRH secretion. Here, we report on data obtained in intact and castrated rats at different ages. The aim was to determine whether the absence of gonads would affect the developmental changes in activation of NMDA receptors that we described recently. In pubertal (50-day-old) rats, orchidectomy resulted in an activation of NMDA receptors which was nonsignificant after 4 days but significant after 13 days. In prepubertal rats orchidectomized at 5 or 10 days and studied 10 days later, the NMDA receptors involved in GnRH secretion were also more activated than in intact animals. Using explants of intact and castrated animals, a similar increase in activation of NMDA receptors was observed between 15 and 25 days of age, a period preceding onset of puberty. Subsequently, between 25 and 50 days, a reduction in NMDA receptor activation was seen. This decrease was observed in intact rats showing normal sexual development and in castrated rats as well.(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]

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See detailEffects of Changes in Nutritional Conditions on Timing of Puberty: Clinical Evidence from Adopted Children and Experimental Studies in the Male Rat
Bourguignon, Jean-Pierre ULg; Gerard, Arlette ULg; Alvarez Gonzalez, Maria-Luz ULg et al

in Hormone Research (1992), 38 Suppl 1(NULL), 97-105

Among 32 patients with idiopathic central precocious puberty seen during a 3-year period, 1/4 were adopted children from developing countries who showed early sexual maturation during the catch-up process ... [more ▼]

Among 32 patients with idiopathic central precocious puberty seen during a 3-year period, 1/4 were adopted children from developing countries who showed early sexual maturation during the catch-up process following their arrival in Belgium. To study the possible mechanism accounting for such clinical observations, we used the male rat as a model, and evaluated the effect of variations in early nutritional conditions, by manipulating litter size, on hypothalamic and testicular maturation. We had shown previously that, in the male rat, onset of puberty was preceded, between 15 and 25 days of age, by a transiently increased activation of N-methyl-D-aspartate receptors involved in a facilitatory control of pulsatile secretion of gonadotropin-releasing hormone. We also showed that the proportion of elongated spermatids in testicular cell homogenates increased between 25 and 45 days of age. When compared to pups of a small litter (6/dam), those of a large litter (14/dam) showed a reduced growth rate (1.9 vs. 3.5 g/day) before weaning (21 days), whereas they grew at a similar rate (5.6 vs. 4.7 g/day) after weaning. At 35 days of age, the animals raised in the large litter showed evidence of delayed hypothalamic and testicular maturation when compared to animals from the small litter. Reduction of litter size at 17 days allowed food-restricted pups of a large litter to resume a normal growth rate before weaning.(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]

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