Exposition continue aux xéno-hormones à faibles doses chez le rat (effets multi-générationnels de mélanges sur les préférences gustatives, le comportement maternel et le développement)

Durant la dernière décennie, la problématique de santé liée aux perturbateurs endocriniens (PE) s est étendue à la toxicité des mélanges. L objectif de ce travail était de définir les conséquences d une exposition continue à des cocktails des PE, à des doses faibles et définies comme non nocives par les autorités réglementaires. Des mélanges associant la génistéine, la vinclozoline, et le Bisphénol A, ont fait l objet d étude intégrative et multi-générationnelle chez le rat qui prend en compte le comportement maternel, le comportement alimentaire et le développement. Nos résultats montrent que ces mélanges peuvent: a) diminuer le comportement maternel, b) modifier les préférences gustatives (sucré, salé), c) affecter le développement dès la période utérine (malformations) jusqu à l âge adulte (surpoids), d) perturber le bilan métabolique (femelles) et l expression par la glande salivaire de gènes codant des protéines impliquées dans la gustation, d engendrer des effets épigénétiques sur sur la génération F2 non exposée. L étude in vitro confirme que la Génistéine et/ou la Vinclozoline, introduites durant l induction de la différenciation adipocytaire affectent le développement des 3T3-L1et leur activité endocrine (leptine; triglycérides), et révèle que la Vinclozoline potentialise l effet anti-adipogénique de la Génistéine.En conclusion, ce travail montre qu une exposition à des mélanges de PE peut altérer le comportement et le développement, et prédisposer l organisme à développer des maladies métaboliques telles que le diabète et l obésité, mais que les propriétés hormonales de chaque composant ne sont pas prédictives des effets cocktailsDuring the last decade, the issue of health-related endocrine disruptors (ED) has been extended to the toxicity of mixtures. The objective of this study was to define the effects of lifelong exposure to ED mixtures, at low doses defined as "non-harmful" by the authorities. In this aim, the effects of mixtures combining genistein, vinclozolin and bisphenol A, have been investigated in the rat by using an integrative and multi-generational experimental approach which takes into account maternal behavior, feeding behavior and development. Our results show that these mixtures could: a) reduce maternal behavior, b) change taste preferences (sweet, salty), c) affect the development from the in utero period (birth defects) up to adulthood (body overweight) d) disrupt the metabolic balance (females) and the salivary gland expression of genes encoding proteins involved in gustation, and e) generate epigenetic effects on the unexposed F2 generation.An in vitro study confirms that Genistein and / or Vinclozolin, introduced at the step of the induction of adipocyte differentiation affect the development and endocrine activity (leptin, triglycerides) of 3T3-L1 cells and reveals that Vinclozolin potentiates the anti-adipogenic effect of Genistein. To conclude, this study shows that exposure to PE mixtures could affect behavior and development, and could predispose the body to develop metabolic diseases such as diabetes and obesity, but the own hormonal properties of component could not be used to predict the cocktails toxicityDIJON-BU Doc.électronique (212319901) / SudocSudocFranceF

Effets de deux xénohormones, la génistéine et la vinclozoline, sur le développement et les fonctions exocrines et endocrines des glandes salivaires submandibulaires de rats Wistar Han (influence de la période d'exposition en fonction de l'âge et du sexe)

Les glandes salivaires sont des glandes mixtes : la salive (produit exocrine) estimpliquée dans le maintien de l homéostasie buccale alors que les secrétions endocrines (ex :facteurs de croissance) ont un rôle physiologique (gamétogénèse, ostéogenèse,hypertension ) Chez les mammifères, elles affichent un dimorphisme sexuel qui laisseentrevoir une sensibilité éventuelle à des xeno-hormones.Ce mémoire présente l action de la génistéine (phyto-oestrogène) et/ou de la vinclozoline(anti-androgène) sur la glande submandibulaire (SM) de rat lors d une exposition précoce viala mère (gestation-lactation) et lors d une exposition pendant la période de croissance (dusevrage à l âge adulte). Les glandes SM, prélevées au stade immature et jeune adulte, ont faitl objet d une analyse histologique et d une étude de marqueurs moléculaire des fonctionsendocrines et exocrines associées aux processus gustatifs. L exposition précoce ralenti ledéveloppement de la glande SM et augmente sélectivement la préférence au sucré des malesimmatures mais pas des adultes ; l analyse moléculaire révèle une action sélective sur lesfonctions exocrines corrélée à celle sur les préférences, ainsi qu une action sur les fonctionsendocrines (facteurs de croissances) qui s inverse avec l âge. L exposition à partir du sevrageperturbe seulement les mâles qui présentent des altérations des structures sécrétrices coupléesà des modifications d expression des récepteurs hormonaux et facteurs de croissance, maisaussi au taux sérique de l EGF.Cette étude identifie la glande submandibulaire comme cible de perturbateurs endocriniens etpose la question des conséquences physiologiques à termeThe salivary glands are mixed glands: saliva (exocrine product) is involved inmaintaining oral homeostasis whereas endocrine secretions (eg growth factors) have aphysiological role (gametogenesis, osteogenesis, hypertension ..). In mammals, they displaysexual dimorphism suggesting a possible susceptibility to xeno-hormones.This manuscript presents the action of genistein (phytoestrogen) and/or vinclozolin (antiandrogenic)on the submandibular gland (SM) rats when performing an early exposure via themother (pregnancy, lactation) or an exposure during the growth period (from weaning toadulthood). The SM glands, collected at immature and young adult ages, have been analyzedaccording histological aspect and expression of molecular markers of endocrine and exocrinefunctions associated with gustatory process. The early exposure disrupted the development ofthe SM gland and selectively increases the sweet preference in immature males but not inadults; molecular analysis reveals a selective action on exocrine functions related to the sweetpreferences and also an action on endocrine functions (growth factors) which reverses withage. Exposure from weaning disrupts only the male salivary glands with alterations insecretory structures coupled with changes in expression of both, sex-hormone receptors andgrowth factors, but also in serum EGF.This study identifies the submandibular gland as a target for endocrine disruptors and raisesthe question of the further physiological consequencesDIJON-BU Doc.électronique (212319901) / SudocSudocFranceF

Conclusions of the French Food Safety Agency on the toxicity of bisphenol A

Since more than 10 years, risk assessment of bisphenol A (BPA) is debated at the international level. In 2008, the U.S. National Toxicology Program (NTP) expressed some concern for adverse effects, at current level of exposure to BPA, on developmental toxicity. In this context, the French Food Safety Agency (AFSSA) decided to review the toxicity data on BPA with a special focus on this endpoint at doses below 5mg/kg bw/day (the no observed adverse effect level set by different regulatory bodies). This paper summarizes the conclusions of a collective assessment conducted by an expert Working Group from AFSSA. Studies were classified into 3 groups: (i) finding no toxicity, (ii) reporting results not considered to be of concern and (iii) indicating warning signals. The term "warning signal" means that no formal conclusion can be drawn regarding the establishment of a health based guidance value but the study raises some questions about the toxicity of BPA at low doses. It was concluded that studies are needed to ascertain the significance for human health of these warning signals and to be able to propose new methodologies for assessing the risks associated with low doses of BPA and more generally of endocrine disruptors

Review of the nutritional benefits and risks related to intense sweeteners

Unfortunately, the original version of this article [1] contained an error. The author’s names were included incorrectly, the surnames were presented before the forename: Bruyère Olivier, Ahmed H. Serge, Atlan Catherine, Belegaud Jacques, Bortolotti Murielle, Canivenc-Lavier Marie-Chantal, Charrière Sybil, Girardet Jean-Philippe, Houdart Sabine, Kalonji Esther, Nadaud Perrine, Rajas Fabienne, Slama Gérard and Margaritis Irène The author list has been corrected in the original article and is also included correctly below: Olivier Bruyère, Serge H. Ahmed, Catherine Atlan, Jacques Belegaud, Murielle Bortolotti, Marie-Chantal Canivenc-Lavier, Sybil Charrière, Jean-Philippe Girardet, Sabine Houdart, Esther Kalonji, Perrine Nadaud, Fabienne Rajas, Gérard Slama, Irène Margaritis (NB: erratum 1 p. doi: in volume 73, 49, published 23 October 2015, (eCollection 2015, PMID: 26500771, PMCID: PMC4619575))International audienceBackground : The intense sweeteners currently authorised in Europe comprise ten compounds of various chemical natures. Their overall use has sharply risen in the last 20 years. These compounds are mainly used to formulate reduced-calorie products while maintaining sweetness.Methods : This extensive analysis of the literature reviews the data currently available on the potential nutritional benefits and risks related to the consumption of products containing intense sweeteners.Results and Conclusions : Regarding nutritional benefits, the available studies, while numerous, do not provide proof that the consumption of artificial sweeteners as sugar substitutes is beneficial in terms of weight management, blood glucose regulation in diabetic subjects or the incidence of type 2 diabetes. Regarding nutritional risks (incidence of type 2 diabetes, habituation to sweetness in adults, cancers, etc.), it is not possible based on the available data to establish a link between the occurrence of these risks and the consumption of artificial sweeteners. However, some studies underline the need to improve knowledge of the links between intense sweeteners consumption and certain risks

Chronic Dietary Exposure to a Low-Dose Mixture of Genistein and Vinclozolin Modifies the Reproductive Axis, Testis Transcriptome, and Fertility

Background: The reproductive consequences and mechanisms of action of chronic exposure to low-dose endocrine disruptors are poorly understood.[br/] Objective: We assessed the effects of a continuous, low-dose exposure to a phytoestrogen (genistein) and/or an antiandrogenic food contaminant (vinclozolin) on the male reproductive tract and fertility.[br/] Methods: Male rats were exposed by gavage to genistein and vinclozolin from conception to adulthood, alone or in combination, at low doses (1 mg/kg/day) or higher doses (10 and 30 mg/kg/day). We studied a number of standard reproductive toxicology end points and also assessed testicular mRNA expression profiles using long-oligonucleotide microarrays.[br/] Results: The low-dose mixture and high-dose vinclozolin produced the most significant alterations in adults: decreased sperm counts, reduced sperm motion parameters, decreased litter sizes, and increased post implantation loss. Testicular mRNA expression profiles for these exposure conditions were strongly correlated. Functional clustering indicated that many of the genes induced belong to the “neuroactive ligand-receptor interactions” family encompassing several hormonally related actors (e.g., follicle-stimulating hormone and its receptor). All exposure conditions decreased the levels of mRNAs involved in ribosome function, indicating probable decreased protein production.[br/] Conclusions: Our study shows that chronic exposure to a mixture of a dose of a phytoestrogen equivalent to that in the human diet and a low dose—albeit not environmental—of a common anti-androgenic food contaminant may seriously affect the male reproductive tract and fertility

Les effets faibles doses : hypothèse d'action

Les effets faibles doses : hypothèse d'actio

Bisphénol A et phtalates : sources d’exposition et niveaux d’imprégnation chez les enfants

Revue invitéeabsen

Modèles biologiques et mathématiques : de la toxicologie à l'écotoxicologie

absen

Impact des conditions environnementales sur la réponse biologique de l’animal de laboratoire : validation de modèles animaux et risques de biais expérimentaux

absen

Bisphénol A : et si c'était aussi une question de goût ?

National audienceLe bisphénol A, élément de base des plastiques en polycarbonate, est aussi un composant du PVC, des vernis internes des canettes et boites de conserves, de plastiques à usages médicaux, d’amalgames dentaires… Il est partout, et fortement suspecté d’avoir une action délétère sur la santé