Mechanisms of endocrine disruption through nuclear receptors and related pathways

International audienceEndocrine-disrupting chemicals (EDCs) are a broad class of molecules present in our environment that are suspected to cause adverse effects in the endocrine system by interfering with the synthesis, transport, degradation, or action of endogenous hormones. Humans are generally exposed to low doses of pollutants, and current researches aim at deciphering the mechanisms accounting for the health impact of EDCs at environmental concentrations. Here, we review different mechanisms through which EDCs might alter hormonal functions by interfering with the nuclear receptors and related pathways, including extranuclear signaling by membrane-bound receptors mediating rapid non-genomic responses, and the aryl hydrocarbon receptor

Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors.

International audience: Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28°C as compared to 37°C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology

Usefulness and pitfalls of MAA SPECT/CT in identifying digestive extrahepatic uptake when planning liver radioembolization

International audiencePURPOSE: Identifying gastroduodenal uptake of (99m)Tc-macroaggregated albumin (MAA), which is associated with an increased risk of ulcer disease, is a crucial part of the therapeutic management of patients undergoing radioembolization for liver tumours. Given this context, the use of MAA single photon emission computed tomography (SPECT)/CT may be essential, but the procedure has still not been thoroughly evaluated. The aim of this retrospective study was to determine the effectiveness of MAA SPECT/CT in identifying digestive extrahepatic uptake, while determining potential diagnostic pitfalls. METHODS: Overall, 139 MAA SPECT/CT scans were performed on 103 patients with different hepatic tumour types. Patients were followed up for at least 6 months according to standard requirements. RESULTS: Digestive, or digestive-like, uptake other than free pertechnetate was identified in 5.7% of cases using planar imaging and in 36.6% of cases using SPECT/CT. Uptake sites identified by SPECT/CT included the gastroduodenal region (3.6%), gall bladder (12.2%), portal vein thrombosis (6.5%), hepatic artery (6.5%), coil embolization site (2.1%) as well as falciform artery (5.0%). For 2.1% of explorations, a coregistration error between SPECT and CT imaging could have led to a false diagnosis by erroneously attributing an uptake site to the stomach or gall bladder, when the uptake actually occurred in the liver. CONCLUSION: SPECT/CT is more efficacious than planar imaging in identifying digestive extrahepatic uptake sites, with extrahepatic uptake observed in one third of scans using the former procedure. However, more than half of the uptake sites in our study were vascular in nature, without therapeutic implications. The risk of coregistration errors must also be kept in mind

Development of new approach methods for the identification and characterization of endocrine metabolic disruptors-a PARC project

In past times, the analysis of endocrine disrupting properties of chemicals has mainly been focused on (anti-)estrogenic or (anti-)androgenic properties, as well as on aspects of steroidogenesis and the modulation of thyroid signaling. More recently, disruption of energy metabolism and related signaling pathways by exogenous substances, so-called metabolism-disrupting chemicals (MDCs) have come into focus. While general effects such as body and organ weight changes are routinely monitored in animal studies, there is a clear lack of mechanistic test systems to determine and characterize the metabolism-disrupting potential of chemicals. In order to contribute to filling this gap, one of the project within EU-funded Partnership for the Assessment of Risks of Chemicals (PARC) aims at developing novel in vitro methods for the detection of endocrine metabolic disruptors. Efforts will comprise projects related to specific signaling pathways, for example, involving mTOR or xenobiotic-sensing nuclear receptors, studies on hepatocytes, adipocytes and pancreatic beta cells covering metabolic and morphological endpoints, as well as metabolism-related zebrafish-based tests as an alternative to classic rodent bioassays. This paper provides an overview of the approaches and methods of these PARC projects and how this will contribute to the improvement of the toxicological toolbox to identify substances with endocrine disrupting properties and to decipher their mechanisms of action

The goliath project: Towards an internationally harmonised approach for testing metabolism disrupting compounds

Copyright © 2020 by the authors. The purpose of this project report is to introduce the European “GOLIATH” project, a new research project which addresses one of the most urgent regulatory needs in the testing of endocrine-disrupting chemicals (EDCs), namely the lack of methods for testing EDCs that disrupt metabolism and metabolic functions. These chemicals collectively referred to as “metabolism disrupting compounds” (MDCs) are natural and anthropogenic chemicals that can promote metabolic changes that can ultimately result in obesity, diabetes, and/or fatty liver in humans. This project report introduces the main approaches of the project and provides a focused review of the evidence of metabolic disruption for selected EDCs. GOLIATH will generate the world’s first integrated approach to testing and assessment (IATA) specifically tailored to MDCs. GOLIATH will focus on the main cellular targets of metabolic disruption—hepatocytes, pancreatic endocrine cells, myocytes and adipocytes—and using an adverse outcome pathway (AOP) framework will provide key information on MDC-related mode of action by incorporating multi-omic analyses and translating results from in silico, in vitro, and in vivo models and assays to adverse metabolic health outcomes in humans at real-life exposures. Given the importance of international acceptance of the developed test methods for regulatory use, GOLIATH will link with ongoing initiatives of the Organisation for Economic Development (OECD) for test method (pre-)validation, IATA, and AOP development

La Vie et l'oeuvre du professeur Eugène Marquis

RENNES1-BU Santé (352382103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

OPTIMISATION DE LA RADIOIMMUNOTHERAPIE METABOLIQUE DES CANCERS BRONCHIQUES HUMAINS (SYSTEME AES, STRUCTURE ET EXPRESSION DU GENE LGALS8 CODANT POUR PO66-CBP)

RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

L’association fait le poison

International audienc

Contribution à l'étude de l'influence du réseau de distribution d'un navire tout électrique sur sa signature électromagnétique

Les installations électriques des navires à passagers et de marchandises ne cessent de se développer avec l'emploi généralisé de la propulsion électrique et l'introduction massive de convertisseurs de puissance. Dans le cas de navires militaires, cette augmentation de la puissance électrique installée ne doit pas compromettre sa " discrétion ", notamment par une signature électromagnétique non contrôlée. Tout en mettant en évidence la circulation de courants ainsi que la présence de tensions en basse fréquence sur le réseau de distribution, l'étude se concentre essentiellement sur les systèmes de propulsion et vise à déterminer les sources de telles perturbations. Une analyse à l'aide de fonctions de commutation permet de mettre en évidence des perturbations basses fréquences dans les différents éléments du système de propulsion. Deux types de convertisseurs sont abordés : commutateurs de courant et onduleurs de tension. Ces montages génèrent des perturbations interharmoniques liées au réseau et à la fréquence de pilotage du moteur de propulsion. Celles-ci sont prévisibles selon les convertisseurs la structure de propulsion (couplages des transformateurs, enroulements statoriques du moteur). Des mesures réalisées à bord de plusieurs navires tout électriques équipés de ces convertisseurs de propulsion valident cette approche. La simulation numérique est utilisée en vue d'avoir un outil de prévision des perturbations des systèmes de propulsion de navires. Toujours par une approche expérimentale, une description des différents courants de fuite provenant d'installations particulières est proposée. La mesure du rayonnement électromagnétique émis par un navire tout électrique de croisière est ensuite présentée et analysée, montrant l'influence des fréquences des sources d'alimentation à bord.Electrical installations aboard passenger and goods vessels keep developing with a more and more frequent use of electric propulsion and the massive introduction of power converters. As far as military ships are concerned the increase of the aboard electrical power must not compromise its 'discretion', especially due to an uncontrolled electromagnetic signature. In enhancing the circulation of currents as well as the presence of voltage in a low frequency range within the distribution network, this study mainly focuses on propulsion systems and aims at finding the sources of such perturbations. A commutation functions based analysis allows to reveal low frequency perturbations in the different parts of the propulsion system. Two kinds of converters are dealt with: current source inverters and voltage source inverters. Both of these drives generate network and propulsion motor driving frequency dependent interharmonic perturbations. These ones are foreseeable according to the kind of converter and to propulsion structure (coupling of the transformers, propulsion motors stator windings). Some measures recorded aboard several all electric ships equipped with this kind of propulsion converters validate this approach. Numeric simulation is used and developed in order to have a tool to predict the perturbations within the propulsion systems and the distribution networks of the electrical ships. Subsequently, in an experimental approach, this work puts forward a description of the different leakage currents coming from several installations. The measure of the electromagnetic signature transmitted by an all electric cruise hip is presented and analysed, showing the influence of the frequencies of the electrical sources onboard.NANTES-BU Sciences (441092104) / SudocNANCY/VANDOEUVRE-INPL (545472102) / SudocSudocFranceF

Structural and functional evidences for the interactions between nuclear hormone receptors and endocrine disruptors at low doses

International audienceEndocrine-disrupting chemicals (EDCs) represent a broad class of exogenous substances that cause adverse effects in the endocrine system mainly by interacting with nuclear hormone receptors (NRs). Humans are generally exposed to low doses of pollutants, and current researches aim at deciphering the mechanisms accounting for the health impact of EDCs at environmental concentrations. Our correlative analysis of structural, interaction and cell-based data has revealed a variety of, sometimes unexpected, binding modes, reflecting a wide range of EDC affinities and specificities. Here, we present a few representative examples to illustrate various means by which EDCs achieve high-affinity binding to NRs. These examples include the binding of the mycoestrogen α-zearalanol to estrogen receptors, the covalent interaction of organotins with the retinoid X- and peroxisome proliferator-activated receptors, and the cooperative binding of two chemicals to the pregnane X receptor. We also discuss some hypotheses that could further explain low-concentration effects of EDCs with weaker affinity towards NRs