References of "Parent, Anne-Simone"
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See detailGPR151, a new regulator of GnRH neurons
Franssen, Delphine ULiege; Lopez Rodriguez, David ULiege; Dupuis, Nadine et al

Poster (2019, September)

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See detailCompound heterozygous mutations in the luteinizing hormone receptor signal peptide causing 46,XY disorder of sex development.
NECHIFOR - POTORAC, Iulia ULiege; Trehan, Ashutosh; Szymanska, Kamila et al

in European journal of endocrinology (2019)

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotrophin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand ... [more ▼]

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotrophin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males. A phenotypically-female patient with pubertal delay, had a 46,XY karyotype and was diagnosed with 46X,Y disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin. cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower molecular weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry. This novel case of 46X,Y DSD illustrates how three different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations. [less ▲]

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See detailEndocrine disrupters and possible contribution to pubertal changes.
FUDVOYE, Julie ULiege; Lopez Rodriguez, David ULiege; Franssen, Delphine ULiege et al

in Best practice & research. Clinical endocrinology & metabolism (2019), 33(3), 101300

The onset of puberty strongly depends on organizational processes taking place during the fetal and early postnatal life. Therefore, exposure to environmental pollutants such as Endocrine disrupting ... [more ▼]

The onset of puberty strongly depends on organizational processes taking place during the fetal and early postnatal life. Therefore, exposure to environmental pollutants such as Endocrine disrupting chemicals (EDCs) during critical periods of development can result in delayed/advanced puberty and long-term reproductive consequences. Human evidence of altered pubertal timing after exposure to endocrine disrupting chemicals is equivocal. However, the age distribution of pubertal signs points to a skewed distribution towards earliness for initial pubertal stages and towards lateness for final pubertal stages. Such distortion of distribution is a recent phenomenon and suggests environmental influences including the possible role of nutrition, stress and endocrine disruptors. Rodent and ovine studies indicate a role of fetal and neonatal exposure to EDCs, along the concept of early origin of health and disease. Such effects involve neuroendocrine mechanisms at the level of the hypothalamus where homeostasis of reproduction is programmed and regulated but also peripheral effects at the level of the gonads or the mammary gland. [less ▲]

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See detailRemembering Jean-Pierre Bourguignon, MD, PhD
Parent, Anne-Simone ULiege; Zoeller, R. Thomas; Geenen, Vincent ULiege et al

E-print/Working paper (2019)

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See detailEffects of exposure to an EDC mixture on the pubertal timing through a maternal behavioral epigenetic multigenerational transmission
Lopez Rodriguez, David ULiege; Delli, Virginia; GERARD, Arlette ULiege et al

Conference (2019)

Endocrine disrupting chemicals (EDCs) are today a rising public health challenge because of their ubiquity and presence in complex mixtures and their effects on the developing body throughout generations ... [more ▼]

Endocrine disrupting chemicals (EDCs) are today a rising public health challenge because of their ubiquity and presence in complex mixtures and their effects on the developing body throughout generations. We aim at studying the effect of a mixture of EDCs on female sexual development during 3 generations of females after exposure and determine whether an epigenetic hypothalamic mechanism is involved in those effects. Female rats were orally exposed from 2 weeks before gestation until weaning to corn oil or a mixture of 14 anti-androgenic and estrogenic EDCs at low doses (F0 generation). Sexual development (vaginal opening, GnRH interpulse interval and estrous cyclicity) as well as maternal behavior were measured from F1 to F3 generation. An RNAseq was carry out using mediobasal hypothalamus from females at P21 from the F1 and F3 generation to decipher targets of the exposure, then validated by RT-PCR and studied for epigenetic modifications by ChIP. F2 and F3 females showed a delayed puberty (delayed VO) and a decrease in the percentage of females having regular estrous cycles, characterized by a significant increase in the time spent in estrus and decreased time spent in diestrus. A hypothalamic epigenetic mechanism is known to be involved in the onset of puberty. We have observed both transcriptional and histone epigenetic alterations in genes involved in estrogen (ESR1), glutamtergic (GRIN2Dà and dopamine (TH and DRD1) signaling as well as in glucocorticoid activity (NR3C1 and CRH), kisspeptin (KISS1) and oxytocin (OXT). We have as well observed that F1 females, exposed in utero, which shows a decrease in TH mRNA expression spent less time licking and more time resting alone. Those modifications on maternal behavior are known to be transmitted through generations. Overall, data shows that gestational exposure to an EDCs mixture can affect maternal behavior and sexual development during several generations. The F1 alteration of maternal behavior caused by in utero exposure to the mixture of EDCs trigger a multigenerational transmission of the phenotype and an induces an altered epigenetic reprogramming if the hypothalamus. [less ▲]

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See detailEDC mixture disrupts maternal behavior and the hypothalamic control of puberty transgenerationally through epigenetic mechanisms.
Lopez Rodriguez, David ULiege; Alwin, Carlos Francisco; GERARD, Arlette ULiege et al

Poster (2019)

Endocrine disrupting chemicals (EDCs) are a rising concern for public health due to their ubiquity as complex mixtures. Our goal was to study the effect of an EDC mixture on female sexual development ... [more ▼]

Endocrine disrupting chemicals (EDCs) are a rising concern for public health due to their ubiquity as complex mixtures. Our goal was to study the effect of an EDC mixture on female sexual development during 3 generations. Female rats (F0 generation) were orally exposed to a mixture of 13 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before gestation until weaning. The mixture was composed of plasticizers, fungicides/pesticides, UV filters, parabens and acetaminophen at doses representing human exposure. Sexual development (vaginal opening, GnRH interpulse-interval, estrous cyclicity and folliculogenesis) and maternal behavior were studied from F0 to F3 generations. At PND21, mediobasal hypothalamus of the F1 and F3 were removed for gene expression, histone modifications and DNA methylation analysis of target genes. F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycle, decreased GnRH interpulse interval and altered late stage folliculogenesis. F1 and F2 females showed decreased maternal licking behavior while spending more time resting alone. The phenotype was associated with transcriptional and epigenetic alterations of hypothalamic genes involved in reproductive competence and behavior like kisspeptin (Kiss1), oxytocin (Oxt), estrogen (Esr1), glutamate (Grin2d), dopamine signaling (Th) as well as glucocorticoid activity (Nr3c1 and Crh). We have found alterations in repressive (H3K27me3, H3K9me3) or active (H3K4me3, H3K9ac) histone marks concomitant with transcriptional activity. Overall, gestational and lactational exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development throughout epigenetic reprogramming of the hypothalamic control of puberty. Such effects could be mediated by alterations of maternal behavior. [less ▲]

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See detailTransgenerational Effects of Exposure to an EDC Mixture on Maternal Behavior and Sexual Development
Lopez Rodriguez, David ULiege; Awylyn, Carlos Francisco; Sevrin, Elena ULiege et al

Conference (2019)

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See detailPersistent vs Transient Alteration of Folliculogenesis and Estrous Cycle After Neonatal vs Adult Exposure to Bisphenol A.
Lopez Rodriguez, David ULiege; Franssen, Delphine ULiege; Sevrin, Elena ULiege et al

in Endocrinology (2019), 160(11), 2558-2572

Exposure to bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical (EDC), is known to produce variable effects on female puberty and ovulation. This variability of effects is possibly due to ... [more ▼]

Exposure to bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical (EDC), is known to produce variable effects on female puberty and ovulation. This variability of effects is possibly due to differences in dose and period of exposure. Little is known about the effects of adult exposure to environmentally relevant doses of this EDC and the differences in effect after neonatal exposure. This study sought to compare the effects of neonatal vs adult exposure to a very low dose or a high dose of BPA for 2 weeks on ovulation and folliculogenesis and to explore the hypothalamic mechanisms involved in such disruption by BPA. One-day-old and 90-day-old female rats received daily subcutaneous injections of corn oil (vehicle) or BPA (25 ng/kg/d or 5 mg/kg/d) for 15 days. Neonatal exposure to both BPA doses significantly disrupted the estrous cycle and induced a decrease in primordial follicles. Effects on estrous cyclicity and folliculogenesis persisted into adulthood, consistent with a disruption of organizational mechanisms. During adult exposure, both doses caused a reversible decrease in antral follicles and corpora lutea. A reversible disruption of the estrous cycle associated with a delay and a decrease in the amplitude of the LH surge was also observed. Alterations of the hypothalamic expression of the clock gene Per1 and the reproductive peptide phoenixin indicated a disruption of the hypothalamic control of the preovulatory LH surge by BPA. [less ▲]

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See detailGrowth hormone (GH) deficient mice with GHRH ablation are severely deficient in vaccine and immune responses against Streptococcus pneumoniae
Farhat, Khalil; Bodart, Gwennaëlle ULiege; Charlet-Renard, Jeanne de Chantal ULiege et al

in Frontiers in Immunology (2018), 9

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene ... [more ▼]

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene (Ghrh−/−) have normal thymus and T-cell development, but present a marked spleen atrophy and B-cell lymphopenia. Therefore, in this paper we have investigated vaccinal and anti-infectious responses of Ghrh−/− mice against S. pneumoniae, a pathogen carrying T-independent antigens. Ghrh−/− mice were unable to trigger production of specific IgM after vaccination with either native pneumococcal polysaccharides (PPS, PPV23) or protein-PPS conjugate (PCV13). GH supplementation of Ghrh−/− mice restored IgM response to PPV23 vaccine but not to PCV13 suggesting that GH could exert a specific impact on the spleen marginal zone that is strongly implicated in T-independent response against pneumococcal polysaccharides. As expected, after administration of low dose of S. pneumoniae, wild type (WT) completely cleared bacteria after 24 h. In marked contrast, Ghrh−/− mice exhibited a dramatic susceptibility to S. pneumoniae infection with a time-dependent increase in lung bacterial load and a lethal bacteraemia already after 24 h. Lungs of infected Ghrh−/− mice were massively infiltrated by inflammatory macrophages and neutrophils, while lung B cells were markedly decreased. The inflammatory transcripts signature was significantly elevated in Ghrh−/− mice. In this animal model, the somatotrope GHRH/GH/IGF1 axis plays a vital and unsuspected role in vaccine and immunological defense against S. pneumoniae. [less ▲]

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See detailPoor growth response during the first year of growth hormone treatment in short prepubertal children with growth hormone deficiency and born small for gestational age: a comparison of different criteria.
Straetemans, Saartje; Thomas, Muriel; Craen, Margarita et al

in International Journal of Pediatric Endocrinology (2018), 2018

Background: There is no consensus on the definition of poor growth response after the first year of growth hormone (GH) treatment. We determined the proportion of poor responders identified by different ... [more ▼]

Background: There is no consensus on the definition of poor growth response after the first year of growth hormone (GH) treatment. We determined the proportion of poor responders identified by different criteria in children with GH deficiency (GHD) and born small for gestational age (SGA). The second aim was to analyze the IGF-1 response in poor growth responders. Methods: First-year height data of 171 SGA and 122 GHD children who remained prepubertal during the first GH treatment year were retrieved from the BESPEED database and analyzed. Criteria for poor first-year response/responsiveness were: change in height (Ht) SDS<0.3 or<0.5, height velocity (HV) SDS<0.5 or <1 based on the population reference, HV SDS<- 1 based on the KIGS expected HV curve (HV Ranke SDS), studentized residual (SR) <- 1 in the KIGS first-year prediction model. Results: Ht SDS<0.5 gave the highest percentage poor responders (37% SGA, 26% GHD). Although % poor responders were comparable for Ht SDS<0.3, HV SDS<+ 0.5, HV SDS<+ 1, SR<- 1, and HV Ranke SDS<- 1, these criteria did not always identify the same patients as poor responders. Among the poor growth responders 24% SGA and 14% GHD patients had an IGF-1 increase < 40%. Conclusions: The different response criteria yield high but comparable percentages poor responders, but identify different patients. This study does not provide evidence that one criterion is better than another. A limited IGF-1 generation is not the major reason for a poor growth response in the first year of GH treatment in SGA and GHD children. Trial registration: Retrospectively registered. [less ▲]

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See detailTransgenerational effects of exposure to an EDC mixture on maternal behavior and sexual development
Lopez Rodriguez, David ULiege; Delli, Virginia; GERARD, Arlette ULiege et al

Conference (2018, July 17)

Environmental factors such as endocrine disrupting chemicals (EDCs) have been proven to produce transgenerational inherited modifications. A rising public health challenge is to determine the effect of ... [more ▼]

Environmental factors such as endocrine disrupting chemicals (EDCs) have been proven to produce transgenerational inherited modifications. A rising public health challenge is to determine the effect of complex mixtures of EDCs on the developing body throughout generations. In this study we aim to determine the transgenerational effects of a mixture of EDCs on female sexual development and behavior. Female rats were orally exposed from 2 weeks before gestation until weaning to corn oil or a mixture of 14 anti-androgenic and estrogenic EDCs at low doses. Sexual development (sex ratio, vaginal opening (VO), GnRH interpulse interval and estrous cyclicity) as well as maternal behavior were measured from F0 to F3 generation. In utero exposed females (F1) when raising pups, showed an increased time resting alone and decreased time licking and grooming pups. F2 (animals whose germlines were exposed) and F3 exposed animals showed an altered sex ratio in favor of males and F2 and F3 females showed delayed VO. F2 and F3 females followed for estrous cyclicity showed significant alterations of estrous cyclicity characterized by a significant increase in the time spent in estrus and decreased time spent in diestrus. F3 females presented an increased GnRH interpulse interval compared to control. Overall, data shows that gestational exposure to an EDCs mixture can affect maternal behavior and sexual development during several generations. The effects observed in the F3 generation suggest the presence of transgenerational epigenetic mechanisms. [less ▲]

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See detailBrain imaging and genetics in patients with congenital hypogonadotropic hypogonadism: a multicenter Belgian study.
VALDES SOCIN, Hernan Gonzalo ULiege; LIBIOULLE, Cécile ULiege; HARVENGT, Julie ULiege et al

in Jorgensen, Jens OL (Ed.) NENEG Abstract Book Communications (2018, April 19)

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See detailNeuroendocrine disruption without direct endocrine mode of action: Polychloro-biphenyls (PCBs) and bisphenol A (BPA) as case studies
Pinson, Anneline ULiege; Franssen, Delphine ULiege; Gerard, Amaury ULiege et al

in Comptes Rendus Biologies (2017), 340(9-10), 432-438

Endocrine disruption is commonly thought to be restricted to a direct endocrine mode of action i.e. the perturbation of the activation of a given type of hormonal receptor by its natural ligand ... [more ▼]

Endocrine disruption is commonly thought to be restricted to a direct endocrine mode of action i.e. the perturbation of the activation of a given type of hormonal receptor by its natural ligand. Consistent with the WHO definition of an endocrine disrupter, a key issue is the “altered function(s) of the endocrine system”. Such altered functions can result from different chemical interactions, beyond agonistic or antagonistic effect at a given receptor. Based on neuroendocrine disruption by polychlorinated biphenyls and bisphenol A, this paper proposes different mechanistic paradigms that can result in adverse health effects. They are a consequence of altered endocrine function(s) secondary to chemical interaction with different steps in the physiological regulatory processes, thus accounting for a possibly indirect endocrine mode of action. © 2017 Académie des sciences [less ▲]

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See detailActivation of the orphan G protein-coupled receptor GPR27 by surrogate ligands promotes β-arrestin 2 recruitment
Dupuis, Nadine ULiege; Laschet, Céline ULiege; Franssen, Delphine ULiege et al

in Molecular Pharmacology (2017), 91(6), 595-608

G protein-coupled receptors are the most important drug targets for human diseases. An important number of them remain devoid of confirmed ligands. GPR27 is one of these orphan receptors, characterized by ... [more ▼]

G protein-coupled receptors are the most important drug targets for human diseases. An important number of them remain devoid of confirmed ligands. GPR27 is one of these orphan receptors, characterized by a high level of conservation among vertebrates and a predominant expression in the central nervous system. In addition, it has recently been linked to insulin secretion. However, the absence of endogenous or surrogate ligands for GPR27 complicates the examination of its biological function. Our aim was to validate GPR27 signaling pathways and therefore we sought to screen a diversity oriented synthesis library to identify GPR27-specific surrogate agonists. In order to select an optimal screening assay, we investigated GPR27 ligand-independent activity. Both in G protein-mediated pathways and in β-arrestin 2 recruitment, no ligand-independent activity could be measured. However, we observed a recruitment of β-arrestin 2 to a GPR27V2 chimera in the presence of membrane-anchored β-adrenergic receptor kinase 1 (GRK2). Therefore, we optimized a firefly luciferase complementation assay to screen against this chimeric receptor. We identified two compounds (N-[4-(anilinocarbonyl)phenyl]-2,4-dichlorobenzamide (ChemBridge ID5128535) and 2,4-dichloro-N-{4-[(1,3-thiazol-2-ylamino)sulfonyl]phenyl}benzamide (ChemBridge ID5217941)) sharing a N-phenyl-2,4-dichlorobenzamide scaffold, which were selective for GPR27 over its closely related family members GPR85 and GPR173. The specificity of the activity was confirmed with a NanoBiT® β-arrestin 2 assay, imaging of GFP-tagged β-arrestin 2 and PathHunter® β-arrestin 2 Assay. Interestingly, no G protein activation was detected upon activation of GPR27 by these compounds. Our study provides the first selective surrogate agonists for the orphan GPR27. [less ▲]

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See detailSecular trends in growth.
FUDVOYE, Julie ULiege; Parent, Anne-Simone ULiege

in Annales d'Endocrinologie (2017), 78(2), 88-91

Human adult height has been increasing world-wide for a century and a half. The rate of increase depends on time and place of measurement. Final height appears to have reached a plateau in Northern ... [more ▼]

Human adult height has been increasing world-wide for a century and a half. The rate of increase depends on time and place of measurement. Final height appears to have reached a plateau in Northern European countries but it is still increasing in southern European countries as well as Japan. While mean birth length has not changed recently in industrialized countries, the secular trend finally observed in adult height mostly originates during the first 2 years of life. Secular trend in growth is a marker of public health and provides insights into the interaction between growth and environment. It has been shown to be affected by income, social status, infections and nutrition. While genetic factors cannot explain such rapid changes in average population height, epigenetic factors could be the link between growth and environment. [less ▲]

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See detailActivational and organizational disruption of folliculogenesis and estrous cycle caused by exposure to Bisphenol A (BPA) during early postnatal or adult life
Lopez Rodriguez, David ULiege; Franssen, Delphine ULiege; GERARD, Arlette ULiege et al

Conference (2017, May 05)

Our previous studies have shown that an early postnatal exposure to a very low dose of bisphenol A (BPA) disrupts sexual maturation and pubertal timing. However, the long-term effects of such low dose ... [more ▼]

Our previous studies have shown that an early postnatal exposure to a very low dose of bisphenol A (BPA) disrupts sexual maturation and pubertal timing. However, the long-term effects of such low dose exposure as well as the effects of adult exposure have not been studied. One day-old and 90 day-old female rats received daily subcutaneous injections of corn oil (vehicle) or BPA (25ng/kg/d or 5mg/kg/d) for 15 days. The early postnatal exposure to both BPA doses significantly decreased the percentage of females with a regular cycle (BPA-25ng: 51±15%; BPA-5mg: 7±7%; OIL: 86±2%). The estrus cycle alterations were characterized by a decrease in time spent in proestrus (BPA-25ng: 13±3%; BPA-5mg: 12±3%; OIL: 18±3%). During adult exposure, both doses caused a disruption of the estrous cycle characterized by a significant decrease in the average time spent in proestrus (BPA-25ng: 19±2%; BPA-5mg: 17±1%; OIL: 23±1%). This effect was transient as the exposed females showed a regular cycle one month after the last dose of BPA. After adult exposure, we also observed a disruption of folliculogenesis characterized by a significant decrease of antral follicles (BPA-25ng: 21±2%; BPA-5mg: 21±2%; OIL: 36±2%) and increase of atretic follicles (BPA-25ng: 24±4%; BPA-5mg: 26±6%; OIL: 15±1%). GnRH secretion measured ex vivo 24h after adult exposure was moderately affected by BPA. Indeed, GnRH interpulse interval was significantly different when comparing animals exposed to the high or low dose of BPA but not when comparingexposed animals to the control group (BPA-25ng: 42.6±0.5; BPA-5mg: 40.2±0.6%; OIL: 41.1±0,2minutes±SEM). In conclusion, while exposure to BPA produces persistent alterations of the estrous cycle after early postnatal exposure, exposure during adulthood appears to cause activational non-persistent alternations of both the estrous cycle and folliculogenesis. [less ▲]

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