Les perturbateurs endocriniens :enjeux pour le consommateur et défis scientifiques

Les perturbateurs endocriniens potentiellement associés à des problèmes de santé publique présentent une multitude d’enjeux sociétaux, législatifs et sanitaires. Actuellement aucune définition officiellement validée ne précise la nature de ces substances et leur cadre d’évaluation peut varier en fonction de leurs usages. Les systèmes endocriniens participent à la régulation de la plupart des fonctions biologiques et ils sont des acteurs clefs du développement et du maintien de l’homéostasie de l’organisme. Des perturbations de leur fonctionnement seront donc associées à de multiples effets sur la santé y compris de façon transgénérationnelle. La complexité de la régulation des différents systèmes hormonaux, de leurs interactions et de leurs effets pour maintenir l’homéostasie de l’organisme est une source de défis scientifiques majeurs. A ceci viennent s’ajouter les notions de faibles doses, de fenêtre de susceptibilité, de relation dose/réponse peu classiques dites non monotones (courbes dose/ réponse en U par exemple) et d’effets différés dans le temps rendant les investigations toxicologiques et épidémiologiques encore plus complexes et parfois en marge des approches de toxicologie classiques. Cette complexité souligne la nécessité d’élaborer des stratégies d’études pluridisciplinaires intégrant tous les niveaux de régulation du vivant jusqu’aux approches de populations

Toward a better understanding of the effects of endocrine disrupting compounds on health : Human-relevant case studies from sheep models

The 3 case studies reviewed in this article were supported by funders including: SRF Academic Scholarship Award 2013, the Wellcome Trust (080388), the European Community’s Seventh Framework Programme under grant agreement no 212885 and French Region Midi-Pyrénées [31000642] the French National Research Program for Environmental and Occupational Health of Anses [grant number 2015/1/112, 2015] and the French National Research Agency [ANR-13-CESA0007-1].Peer reviewedPostprin

Changes in the 5-HT2(A )receptor system in the pre-mammillary hypothalamus of the ewe are related to regulation of LH pulsatile secretion by an endogenous circannual rhythm

BACKGROUND: We wanted to determine if changes in the expression of serotonin 2A receptor (5HT2(A )receptor) gene in the premammillary hypothalamus are associated with changes in reproductive neuroendocrine status. Thus, we compared 2 groups of ovariectomized-estradiol-treated ewes that expressed high vs low LH pulsatility in two different paradigms (2 groups per paradigm): (a) refractoriness (low LH secretion) or not (high LH secretion) to short days in pineal-intact Ile-de-France ewes (RSD) and (b) endogenous circannual rhythm (ECR) in free-running pinealectomized Suffolk ewes in the active or inactive stage of their reproductive rhythm. RESULTS: In RSD ewes, density of 5HT2(A )receptor mRNA (by in situ hybridization) was significantly higher in the high LH group (25.3 ± 1.4 vs 21.4 ± 1.5 grains/neuron, P < 0.05) and (3)H-Ketanserin binding (a specific radioligand) of the median part of the premammillary hypothalamus tended to be higher in the high group (29.1 ± 4.0 vs 24.6 ± 4.2 fmol/mg tissu-equivalent; P < 0.10). In ECR ewes, density of 5HT2(A )receptor mRNA and (3)H-Ketanserin binding were both significantly higher in the high LH group (20.8 ± 1.6 vs 17.0 ± 1.5 grains/neuron, P < 0.01, and 19.7 ± 5.0 vs 7.4 ± 3.4 fmol/mg tissu-equivalent; P < 0.05, respectively). CONCLUSIONS: We conclude that these higher 5HT2(A )receptor gene expression and binding activity of 5HT2(A )receptor in the premammillary hypothalamus are associated with stimulation of LH pulsatility expressed before the development of refractoriness to short days and prior to the decline of reproductive neuroendocrine activity during expression of the endogenous circannual rhythm

Maternal and Fetal Exposure to Bisphenol A Is Associated with Alterations of Thyroid Function in Pregnant Ewes and Their Newborn Lambs

The putative thyroid-disrupting properties of bisphenol A (BPA) highlight the need for an evaluation of fetal exposure and its consequence on the mother/newborn thyroid functions in models relevant to human. The goals of this study were to characterize in sheep a relevant model for human pregnancy and thyroid physiology, the internal exposures of the fetuses and their mothers to BPA and its main metabolite BPA-glucuronide (Gluc), and to determine to what extent it might be associated with thyroid disruption. Ewes were treated with BPA [5 mg/(kg . d) sc] or vehicle from d 28 until the end of pregnancy. Unconjugated BPA did not appear to accumulate in pregnant ewes, and its concentration was similar in the newborns and their mothers (0.13 +/- 0.02 and 0.18 +/- 0.03 nmol/ml in cord and maternal blood, respectively). In amniotic fluid and cord blood, BPA-Gluc concentrations were about 1300-fold higher than those of BPA. Total T-4 concentrations were decreased in BPA-treated pregnant ewes and in the cord and the jugular blood of their newborns (30% decrease). A similar difference was observed for free T-4 plasma concentrations in the jugular blood of the newborns. Our results show in a long-gestation species with a similar regulatory scheme of thyroid function as humans that BPA in utero exposure can be associated with hypothyroidism in the newborns. If such an effect were to be confirmed for a more relevant exposure scheme to BPA, this would constitute a major issue for BPA risk assessment

Prion protein in the cerebrospinal fluid of healthy and naturally scrapie-affected sheep

The aim of this study was to characterize the cerebrospinal fluid (CSF) prion protein (PrP) of healthy and naturally scrapie-affected sheep. The soluble form of CSF PrPC immunoblotted with an anti-octarepeat and an anti-C terminus mAb showed two isoforms of approximately 33 and 26 kDa, corresponding to the biglycosylated and unglycosylated isoforms of brain PrPC. Neither the mean concentration nor the electrophoretic profile of CSF PrP differed between healthy and scrapieaffected sheep, whereas a slightly increased resistance of CSF PrP to mild proteolysis by proteinase K was evident in the CSF of scrapie-affected sheep. No difference in susceptibility to proteolysis was observed between the two ARR and VRQ genetic variants of the purified prokaryote recombinant PrP. It was concluded that the physicochemical properties of PrPC in the CSF could be altered during scrapie and that these changes might reflect the physiopathological process of prion disease

Régulation de la secrétion pulsatile de LHRH par la photopériode et la mélatonine chez la brebis : mise en évidence et caractérisation d'une étape dopaminergique

* INRA, centre de Tours Diffusion du document : INRA, centre de Tours Diplôme : Dr. d'Universit

5.9. Les perturbateurs endocriniens

Dans les dernières décennies, des données expérimentales et observationnelles se sont accumulées pour étayer l’hypothèse associant des contaminants environnementaux et/ou alimentaires à des effets délétères sur les systèmes hormonaux des animaux et de l’homme. Une définition des perturbateurs endocriniens (PE) a été établie par une instance internationale comme l’OMS : « substances ou mélanges exogènes qui altèrent la ou les fonction(s) du système endocrinien conduisant à des effets adverses ..

Régulation de la secrétion pulsatile de LHRH par la photopériode et la mélatonine chez la brebis : mise en évidence et caractérisation d'une étape dopaminergique

* INRA, centre de Tours Diffusion du document : INRA, centre de Tours Diplôme : Dr. d'Universit

Regulation of luteinizing hormone-releasing hormone (LHRH) secretion by melatonin in the ewes. I. Stimultaneous delayed increaese in LHRH and luteinizing hormone pulsatile secretion

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