HAL du Programme national de recherche environnement-santé-travail (PNR EST)
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Interspecies Differences in Activation of Peroxisome Proliferator-Activated Receptor γ by Pharmaceutical and Environmental Chemicals
No full textInternational audienceEndocrine disrupting chemicals (EDCs) are able to deregulate the hormone system, notably through interactions with nuclear receptors (NRs). The mechanisms of action and biological effects of many EDCs have mainly been tested on human and mouse but other species such as zebrafish and xenopus are increasingly used as a model to study the effects of EDCs. Among NRs, peroxisome proliferator-activated receptor γ (PPARγ) is a main target of EDCs, for which most experimental data have been obtained from human and mouse models. To assess interspecies differences, we tested known human PPARγ ligands on reporter cell lines expressing either human, mouse, zebrafish, or xenopus PPARγ. Using these cell lines, we were able to highlight major interspecies differences. Known hPPARγ pharmaceutical ligands modulated hPPARγ and mPPARγ activities in a similar manner, while xPPARγ was less responsive and zfPPARγ was not modulated at all by these compounds. On the contrary, human liver X receptor (hLXR) ligands GW 3965 and WAY-252623 were only active on zfPPARγ. Among environmental compounds, several molecules activated the PPARγ of the four species similarly, e.g., phthalates (MEHP), perfluorinated compounds (PFOA, PFOS), and halogenated derivatives of BPA (TBBPA, TCBPA), but some of them like diclofenac and the organophosphorus compounds tri-o-tolyl phosphate and triphenyl phosphate were most active on zfPPARγ. This study confirms or shows for the first time the h, m, x, and zfPPARγ activities of several chemicals and demonstrates the importance of the use of species-specific models to study endocrine and metabolism disruption by environmental chemicals.</div
Simultaneous analysis of PAH urinary mono- and dihydroxylated metabolites by GC-MS-MS following SPE and two-stage derivatization
No full textInternational audienceA new gas chromatography-tandem mass spectrometry method for the determination of mono-and dihydroxylated polycyclic aromatic hydrocarbon metabolites (OH-PAHs and diol-PAHs) in urine was developed and validated. Various sample preparation procedures were compared, namely liquid-liquid extraction (LLE), dispersive solid-phase extraction (dSPE), and SPE, alone or combined. A novel two-stage derivatization approach using 2 silylation reagents was developed, and an experimental procedure design was used to optimize the programmed temperature vaporization-solvent vent injection (PTV-SV) GC parameters. The method focused on 11 target compounds resulting from four-to five-ring suspected carcinogenic PAHs. SPE was identified as an acceptable and more convenient extraction method for all tested metabolites, with extraction rates ranging from 63 to 86% and relative standard deviations lower than 20%. The two-stage derivatization approach successfully allowed first the derivatization of OH-PAHs by MTBSTFA (N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide) and then diol-PAHs by BSTFA (N,Obis(trimethylsilyl)trifluoroacetamide) in a single run. The limits of quantification were in the range of 0.01-0.02 μg l −1 for OH-PAHs and 0.02-0.2 μg l −1 for diol-PAHs. The intra-and interday precisions were lower than 10%. The method was applied to determine PAH metabolites in urine collected at the beginning and at the end of the working week from 6 workers involved in aluminum production. The mean diol-PAH levels at the end of the week were 10 to 20 times higher (0.86-2.34 μg g −1 creatinine) than those of OH-PAHs (0.03-0.30 μg g −1). These results confirmed the usefulness of this new analytical technique for detecting and characterizing metabolic patterns of PAHs in urine and assessing carcinogenic occupational exposures
Mitochondrial Dysfunction as a Hallmark of Environmental Injury
No full textInternational audienceEnvironmental factors including diet, sedentary lifestyle and exposure to pollutants largely influence human health throughout life. Cellular and molecular events triggered by an exposure to environmental pollutants are extremely variable and depend on the age, the chronicity and the doses of exposure. Only a fraction of all relevant mechanisms involved in the onset and progression of pathologies in response to toxicants has probably been identified. Mitochondria are central hubs of metabolic and cell signaling responsible for a large variety of biochemical processes, including oxidative stress, metabolite production, energy transduction, hormone synthesis, and apoptosis. Growing evidence highlights mitochondrial dysfunction as a major hallmark of environmental insults. Here, we present mitochondria as crucial organelles for healthy metabolic homeostasis and whose dysfunction induces critical adverse effects. Then, we review the multiple mechanisms of action of pollutants causing mitochondrial toxicity in link with chronic diseases. We propose the Aryl hydrocarbon Receptor (AhR) as a model of “exposome receptor”, whose activation by environmental pollutants leads to various toxic events through mitochondrial dysfunction. Finally, we provide some remarks related to mitotoxicity and risk assessmen
Co-expression network analysis identifies novel molecular pathways associated with cadmium and pyriproxyfen testicular toxicity in Gammarus fossarum
No full textInternational audienceOmics approaches are continuously providing new clues on the mechanisms of action of contaminants in species of environmental relevance, contributing to the emergence of molecular ecotoxicology. Co-expression network approaches represent a suitable methodological framework for studying the rich content of omics datasets. This study aimed to find evidence of key pathways and proteins related to the testicular toxicity in the sentinel crustacean species Gammarus fossarum exposed to endocrine disruptors using a weighted protein co-expression network analysis. From a shotgun proteomics dataset of male gonads of G. fossarum organisms exposed to cadmium (Cd), pyriproxyfen (Pyr) and methoxyfenozide (Met) in laboratory conditions, four distinct modules were identified as significantly correlated to contaminants' exposure. Protein set enrichment analysis identified modules involved in cytoskeleton organization and oxidative stress response associated with the Cd exposure. The module associated with Pyr exposure was associated with endoplasmic reticulum stress (ER) response, and the module correlated with Met exposure was characterized by a significant proportion of amphipod-restricted proteins whose functions are still not characterized. Our results show that co-expression networks are efficient and adapted tools to identify new potential mode of actions from environmental sentinel species, such as G. fossarum, using a proteogenomic approach, even without an annotated genome
Alors, elle est polluée ma rivière ? Enjeux et opportunités de l’expertise scientifique interdisciplinaire
No full textInternational audience« Alors, elle est polluée la rivière ? » Cette question, apparemment simple et banale, illustre à elle seule la complexité de l’expertise scientifique dans le domaine des sciences de l’environnement. Elle nous est posée de manière quasi-systématique par les différents usagers des bords de rivières (promeneurs, pêcheurs…). Répondre à cette question nécessite de s’interroger sur ce qui est attendu par le public en terme d’expertise et de communication autour de cette expertise. Au travers de trois études, nous présenterons des questionnements à l’interface sciences & société
Caractérisation des effets d'une contamination complexe par les pesticides d'un petit cours d'eau vosgien emblématique (Cleurie) : une approche interdisciplinaire basée sur les biofilms phototrophes
No full textNational audienceLa Directive Cadre sur l’Eau impose l’atteinte ou le maintien du bon état écologique des masses d’eau. Il s’avère donc indispensable de disposer d’indicateurs précoces de la qualité des masses d’eau en conditions naturelles. Si de nombreux indicateurs existent, ils ne sont pas toujours en mesure de révéler les effets subtils d’une faible pression épisodique sur des temps d’exposition longs. Il est donc nécessaire de développer de nouveaux indicateurs, complémentaires de ceux actuels mais plus à même de traduire l’impact des contaminants chimiques, notamment les pesticides. Pour ce faire, les biofilms phototrophes présentent un large éventail de descripteurs structurels et fonctionnels pertinents pour le diagnostic environnemental.La contamination observée depuis plusieurs années dans la rivière Cleurie (Région Grand-Est, Vosges) constitue un cadre de travail idéal pour éprouver la sensibilité de ces indicateurs. En raison d’activités industrielles (textiles), ce petit cours d’eau vosgien de tête de bassin versant forestier présente un cocktail complexe de molécules, chroniques et épisodiques (du quotidien au saisonnier) mais en dessous des normes de qualité environnementales. Ce cocktail se caractérise par de fortes concentrations en glyphosate et son principal produit de dégradation, l’acide aminométhylphosphonique (AMPA) ainsi qu'une forte charge de matière organique dissoute (MO) dominée par des colorants et azurants optiques. Dans ce contexte notre objectif est d’estimer les potentiels effets écotoxiques et fonctionnels in situ de cette contamination complexe et d’identifier si ces effets sont liés au rejet de glyphosate et d’AMPA dans la Cleurie. Les résultats générés contribueront à une approche sociologique qui sera développée en parallèle pour suivre la circulation des savoirs scientifiques produits entre les différents acteurs (scientifiques, pouvoirs publics, citoyens…) impliqués dans une controverse locale mais qui s’inscrit dans celle plus générale et ancienne sur la toxicité des pesticides.Différentes stations ont été identifiées le long du linéaire de la Cleurie et un suivi annuel de la structure (biodiversité, déformations) et du fonctionnement (approche PICT-Pollution Induced Community Tolerance) des biofilms phototrophes a été initié. Parallèlement à cette approche de terrain, des bioessais ont été réalisés pour évaluer la toxicité du glyphosate sur les diatomées en conditions standardisées. Pour ce faire, les deux espèces Nitzschia palea et Gomphonema gracile ont été exposées pendant 7j à une large gamme de concentration de glyphosate (0,4-84 mg/L). Dans un second temps, les deux espèces ont été exposées sur une durée plus longue (28j) afin d’évaluer le potentiel tératogène du glyphosate sur la morphologie des frustules. Ces premiers résultats semblent indiquer que la déformation des diatomées benthiques et l'acquisition de tolérance au glyphosate par les biofilms constitueraient des marqueurs plus sensibles que les indices structurels classiques (IBD...) quant à la présence de glyphosate et d’AMPA le long du linéaire du cours d’eau
Microorganisms Associated with Mosquito Oviposition Sites: Implications for Habitat Selection and Insect Life Histories
No full textInternational audienceMosquitoes are considered one of the most important threats worldwide due to their ability to vector pathogens. They are responsible for the transmission of major pathogens such as malaria, dengue, zika, or chikungunya. Due to the lack of treatments or prophylaxis against many of the transmitted pathogens and an increasing prevalence of mosquito resistance to insecticides and drugs available, alternative strategies are now being explored. Some of these involve the use of microorganisms as promising agent to limit the fitness of mosquitoes, attract or repel them, and decrease the replication and transmission of pathogenic agents. In recent years, the importance of microorganisms colonizing the habitat of mosquitoes has particularly been investigated since they appeared to play major roles in their development and diseases transmission. In this issue, we will synthesize researches investigating how microorganisms present within water habitats may influence breeding site selection and oviposition strategies of gravid mosquito females. We will also highlight the impact of such microbes on the fate of females’ progeny during their immature stages with a specific focus on egg hatching, development rate, and larvae or pupae survival
Residential exposure to natural background radiation at birth and risk of childhood acute leukemia in France, 1990-2009
No full textInternational audienceBackground: The role of natural background radiation (NBR) in childhood acute leukaemias (AL) remains unclear. Several large record based studies have recently reported heterogeneous results. The different exposure period considered in these studies may explain this heterogeneity. Objectives: In a previous ecological study we did not observe any association between childhood AL incidence in France and NBR exposure at the time of diagnosis. With the same methodology, the present study focused on NBR exposure during the prenatal period. Methods: The study population included all children born in mainland France between 1990 and 2009 (French residents). Based on the French national registry of childhood cancer, we included 5,932 childhood AL cases born and diagnosed during the study period. NBR levels in municipalities of residence at birth were estimated by cokriging models, using NBR measurements and precise geological data. The incidence rate ratio (IRR) per unit variation of exposure was estimated with Poisson regression models, with adjustment for socio-demographic indicators and ultraviolet radiation levels. NBR exposures were considered at the time of birth, and cumulatively from birth to diagnosis. We also estimated a total NBR dose to red-bone marrow. We analyzed all AL together, and the main types of AL separately.Results: There was no association between NBR exposure at birth and childhood AL incidence, neither overall (gamma radiation: IRR = 0.98 (0.93,1.04) per 50 nSv/h; radon concentration: IRR = 0.96 (0,90,1.02) per 100 Bq/m3) nor for the main AL types. The conclusions were similar with the cumulative exposures, and the total red-bone marrow dose. Conclusions: The study was based on high quality incidence data, large numbers of AL cases, and validated models of NBR exposure assessment. In all, the results further support the hypothesis that NBR are not associated to childhood AL in France, whatever the timing for exposure assessment
The ligand-bound state of a G protein-coupled receptor stabilizes the interaction of functional cholesterol molecules
No full textInternational audienceCholesterol is a major component of mammalian plasma membranes that affects the physical properties of the lipid bilayer but also the function of many membrane proteins including G protein-coupled receptors (GPCRs). The oxytocin receptor (OXTR) is involved in parturition and lactation of mammals, and in their emotional and social behaviors. Cholesterol acts on OXTR as an allosteric modulator inducing a high-affinity state for orthosteric ligands through a molecular mechanism that has yet to be determined. Using the ion channel-coupled receptor (ICCR) technology, we developed a functional assay of cholesterol modulation of GPCRs that is independent of intracellular signaling pathways and operational in living cells. Using this assay, we discovered a stable binding of cholesterol molecules to the receptor when it adopts an orthosteric ligand-bound state. This stable interaction preserves the cholesterol-dependent activity of the receptor in cholesterol-depleted membranes. This mechanism was confirmed using time-resolved FRET (TR-FRET) experiments on WT OXTR expressed in CHO cells. Consequently, a positive cross-regulation sequentially occurs in OXTR between cholesterol and orthosteric ligands. The possibility to selectively stabilize the interaction of functional cholesterol molecules, also offers new opportunities for the challenging identification of the functional cholesterol binding site(s) and for deeper understanding of the molecular mechanisms
Vineyards, but not cities, are associated with lower presence of a generalist bird, the Common Blackbird (Turdus merula), in Western France
No full textInternational audienceBackground Land-use change is one of the main drivers of the global erosion of biodiversity. In that context, it is crucial to understand how landscape characteristics drive the presence of rare endangered species. Nevertheless, it is also important to study common species in multiple habitats, because they represent a large proportion of biodiversity and are essential to maintain ecological functions. Interestingly, some habitats, as farmlands with permanent crops (e.g. vineyards), have been overlooked in the literature. Methods In this study, we investigated the distribution of a widespread and common bird species, the Common Blackbird ( Turdus merula ), within and between the three main habitats of our study area (rural Western France). We specifically focused on (1) woodlands, (2) farmlands with a high vineyard coverage, and (3) moderately urbanized areas. Specifically, we aimed to assess the beneficial and detrimental effects of these habitats and their fine-scale composition on the presence of a common bird species, relying on a survey by point counts (nearly 100 locations). We studied the effects of habitats and gradients of fine-scale habitat composition on blackbird presence using logistic regression analyses. Results Blackbirds were present in all studied habitats. However, their presence varied between habitats, being lower in vineyards than in woodlands and cities. In woodlands and cities, fine-scale analyses did not reveal any component driving the species’ presence. However, we found that shrub and tree vegetation cover had a significant positive effect on blackbird presence in vineyards. Conclusions Our results are in agreement with the definition of a generalist species. Interestingly, species distribution varied between habitats. The high presence of blackbirds in urban areas suggests that medium-sized cities, despite their artificialization, do not constrain the settlement of this former forest specialist and that green spaces may allow blackbirds to thrive in medium-sized cities. On the contrary, we found an impoverished presence of blackbirds in vineyards and a positive effect of vegetation on their presence in these landscapes. This suggests that permanent crops, and more generally farmlands, may impose important constraints to common species. Future studies should examine how to enhance biodiversity through agricultural management policies, especially in vineyards