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1. A dual mixture of persistent organic pollutants modifies carbohydrate metabolism in the human hepatic cell line HepaRG

Author

Eléonore A. Attignon, Dimosthenis Sarigiannis, Robert Barouki, Emilie Distel, Sylvie Bortoli, Alix F. Leblanc, Xavier Coumoul, Martine Aggerbeck, Etienne Blanc, Spyros Karakitsios, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Université de Paris (UP)

Subjects
Polychlorinated Dibenzodioxins, [SDV]Life Sciences [q-bio], 010501 environmental sciences, Carbohydrate metabolism, 01 natural sciences, Biochemistry, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Toxicity Tests, Constitutive androstane receptor, Humans, 030212 general & internal medicine, Receptor, Ecosystem, 0105 earth and related environmental sciences, General Environmental Science, Pregnane X receptor, Glycogen, biology, Chemistry, Aryl hydrocarbon receptor, 13. Climate action, Hepatocytes, biology.protein, Carbohydrate Metabolism, Environmental Pollutants, Signal transduction, Xenobiotic
Abstract

Individuals as well as entire ecosystems are exposed to mixtures of Persistent Organic Pollutants (POPs). Previously, we showed, by a non-targeted approach, that the expression of several genes involved in carbohydrate metabolism was almost completely inhibited in the human hepatic cell line HepaRG following exposure to a mixture of the organochlorine insecticide alpha-endosulfan and 2,3,7,8 tetrachlorodibenzo-p-dioxin. In this European HEALS project, which studies the effects of the exposome on human health, we used a Physiologically Based BioKinetic model to compare the concentrations previously used in vitro with in vivo exposures for humans. We investigated the effects of these POPs on the levels of proteins, on glycogen content, glucose production and the oxidation of glucose into CO2 and correlated them to the expression of genes involved in carbohydrate metabolism as measured by RT-qPCR. Exposure to individual POPs and the mixture decreased the expression of the proteins investigated as well as glucose output (up to 82%), glucose oxidation (up to 29%) and glycogen content (up to 48%). siRNAs that specifically inhibit the expression of several xenobiotic receptors were used to assess receptor involvement in the effects of the POPs. In the HepaRG model, we demonstrate that the effects are mediated by the aryl hydrocarbon receptor and the estrogen receptor alpha, but not the pregnane X receptor or the constitutive androstane receptor. These results provide evidence that exposure to combinations of POPs, acting through different signaling pathways, may affect, more profoundly than single pollutants alone, metabolic pathways such as carbohydrate/energy metabolism and play a potential role in pollutant associated metabolic disorders.

Published
2019
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2. Chronic Exposure to Low Doses of Dioxin Promotes Liver Fibrosis Development in the C57BL/6J Diet-Induced Obesity Mouse Model

Author

Xavier Coumoul, Caroline Duval, Alix F. Leblanc, Fatima Teixeira-Clerc, Claude Emond, Michèle Guerre-Millo, Sophie Lotersztajn, Robert Barouki, Sothea Touch, Martine Aggerbeck, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Hôpital Henri Mondor, Université Paris-Est (UPE), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Dissemin, Projet

Subjects
0301 basic medicine, Chronic exposure, Liver Cirrhosis, medicine.medical_specialty, genetic structures, Health, Toxicology and Mutagenesis, Liver fibrosis, [SDV]Life Sciences [q-bio], Physiology, 010501 environmental sciences, Biology, C57bl 6j, Dioxins, behavioral disciplines and activities, 01 natural sciences, 03 medical and health sciences, Mice, Fibrosis, Internal medicine, medicine, Animals, Toxicity Tests, Chronic, 0105 earth and related environmental sciences, 2. Zero hunger, urogenital system, Research, Low dose, Public Health, Environmental and Occupational Health, medicine.disease, Obesity, dissemin, 3. Good health, body regions, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, 13. Climate action, Environmental Pollutants, psychological phenomena and processes
Abstract

Background: Exposure to persistent organic pollutants (POPs) has been associated with the progression of chronic liver diseases, yet the contribution of POPs to the development of fibrosis in non-alcoholic fatty liver disease (NAFLD), a condition closely linked to obesity, remains poorly documented. Objectives: We investigated the effects of subchronic exposure to low doses of the POP 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor ligand, on NAFLD progression in diet-induced obese C57BL/6J mice. Methods: Male C57BL/6J mice were fed either a 10% low-fat (LFD) or a 45% high-fat (HFD) purified diet for 14 weeks and TCDD-exposed groups were injected once a week with 5 μg/kg TCDD or the vehicle for the last 6 weeks of the diet. Results: Liver histology and triglyceride levels showed that exposure of HFD fed mice to TCDD worsened hepatic steatosis, as compared to either HFD alone or LFD plus TCDD and the mRNA levels of key genes of hepatic lipid metabolism were strongly altered in co-treated mice. Further, increased liver collagen staining and serum transaminase levels showed that TCDD induced liver fibrosis in the HFD fed mice. TCDD in LFD fed mice increased the expression of several inflammation and fibrosis marker genes with no additional effect from a HFD. Conclusions: Exposure to TCDD amplifies the impairment of liver functions observed in mice fed an enriched fat diet as compared to a low fat diet. The results provide new evidence that environmental pollutants promote the development of liver fibrosis in obesity-related NAFLD in C57BL/6J mice. Citation: Duval C, Teixeira-Clerc F, Leblanc AF, Touch S, Emond C, Guerre-Millo M, Lotersztajn S, Barouki R, Aggerbeck M, Coumoul X. 2017. Chronic exposure to low doses of dioxin promotes liver fibrosis development in the C57BL/6J diet-induced obesity mouse model. Environ Health Perspect 125:428–436; http://dx.doi.org/10.1289/EHP316

Published
2016
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3. Dihydroquinoline derivatives as redox chemical delivery systems (CDS) or 'bio-oxidisable' prodrugs for brain delivery of acetylcholinesterase inhibitors : design, synthesis, [11C] radiosynthesis and biological evaluation

Author

Bohn, P, Gourand, F, Papamicaël, C, Ibazizène, M, Dhilly, M, Gembus, V, Alix, F, Tîntas, Ml, Marsais, F, Barré, L, Levacher, V, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Brunaud, Carole

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], [CHIM] Chemical Sciences, [CHIM.RADIO] Chemical Sciences/Radiochemistry, [CHIM]Chemical Sciences, [CHIM.RADIO]Chemical Sciences/Radiochemistry
Abstract

LDM TEP; International audience

Published
2015

4. Dihydroquinoline Carbamate Derivatives as 'Bio-oxidizable' Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [¹¹C] Radiosynthesis and Biological Evaluation

Author

Bohn, Pierre, Gourand, F., Papamicaël, Cyril, Ibazizène, M., Dhilly, M, Gembus, Vincent, Alix, F., Tîntas, Mihaela-Liliana, Marsais, Francis, Barré, Louise, Levacher, Vincent, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Développements Méthodologiques en Tomographie par Emission de Positons (LDM-TEP), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), VFP Therapies Drugs : Highway to the Brain, Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT)

Subjects
[SDV]Life Sciences [q-bio], prodrug, Alzheimer’s disease, central acetylcholinesterase inhibitors, cyclic rivastigmine analogues, 11C-radiolabeling
Abstract

LDM TEP COLL; International audience; With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer’s disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biological evaluation of new central AChE inhibitors based on an original “bio-oxidizable” prodrug strategy. After peripheral injection of the prodrug (1a) [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug (2a) [IC50 = 20 nM (hAChE)] through central redox activation of (1a). Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent positive charge in (2a) promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug 1a was developed for additional ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [11C] (1a), while identification of [11C] (2a) and [11C] (3a) both accounts for central redox activation of (1a) and pseudoirreversible inhibition of AChE, respectively. Finally, Caco-2 permeability assays predicted metabolite (3a) as a substrate for efflux transporters (P-gp inter alia), suggesting that metabolite (3a) might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this “bio-oxidizable” prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors.

Published
2015
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5. Two persistent organic pollutants which act through different xenosensors (alpha-endosulfan and 2,3,7,8 tetrachlorodibenzo-p-dioxin) interact in a mixture and downregulate multiple genes involved in human hepatocyte lipid and glucose metabolism

Author

Sébastien Jacques, Nicolas Cagnard, Franck Letourneur, Martine Aggerbeck, Robert Barouki, Christiane Guguen-Guillouzo, Alix F. Leblanc, Ariane Ambolet-Camoit, Min Ji Kim, Chris Ottolenghi, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This work was supported by ANR (Agence Nationale pour la Recherche) [06SETS26, Oncopop], Association de la Recherche sur le Cancer [ARC-3927], INSERM (Institut National de la Santé et de la Recherche Médicale), Université Paris Descartes, MESR (Ministère de l’Enseignement Supérieur et de la Recherche) (doctoral fellowships, Ariane Ambolet-Camoit, Alix Leblanc), and the European Union's Seventh Programme for research, technological development and demonstration (HEALS project, grant agreement Number. 603946)., ANR-06-SEST-0026,ONCOPOP,Polluants Organiques persistants (POP)_ Migration cellulaire et progression tumorale(2006), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANR-06-SEST-0026,ONCOPOP,Polluants Organiques persistants (POP)_ Migration cellulaire et progression tumorale ( 2006 ), Jonchère, Laurent, Programme Santé-Environnement et Santé-Travail (SEST) - Polluants Organiques persistants (POP)_ Migration cellulaire et progression tumorale - - ONCOPOP2006 - ANR-06-SEST-0026 - SEST - VALID, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Polychlorinated Dibenzodioxins, genetic structures, medicine.drug_class, [SDV]Life Sciences [q-bio], Blotting, Western, Biology, Retinoid X receptor, Biochemistry, Cell Line, chemistry.chemical_compound, Gene expression, medicine, Humans, Retinoid, Pesticides, Gene, [ SDV ] Life Sciences [q-bio], General Medicine, Metabolism, dioxin, Lipid Metabolism, [SDV] Life Sciences [q-bio], mixture, Metabolic pathway, medicine.anatomical_structure, Glucose, chemistry, 13. Climate action, Hepatocyte, Hepatocytes, HepaRG, Xenobiotic, metabolism, microarray, Endosulfan
Abstract

Individuals, typically, are exposed to mixtures of environmental xenobiotics affecting multiple organs and acting through different xenosensors and pathways in species and cell-type specific manners. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and α-endosulfan are Persistent Organic Pollutants (POPs) and endocrine disruptors which act through different xenosensors and accumulate in the liver. Our objective in this HEALS study was to investigate the effects of the mixture of these POPs on gene expression in a human-derived hepatocyte cell line, HepaRG. We found that, in spite of having largely uncorrelated effects, TCDD and α-endosulfan, when mixed, alter the expression of genes. The combined effects of the mixture of the POPs significantly altered the expression of 100 genes (42 up- and 58 down-regulated) whereas the same concentration of either POP alone did not alter significantly the expression of these genes. For 32 other genes, selective inhibitory crosstalk between TCDD and α-endosulfan was observed. One of the POPs inhibited the effect, on gene expression, of the other in the mixture although, when used alone, that POP did not affect expression. The expression of another 82 genes was significantly altered (up- or down-regulated) by a single POP. The addition of the second POP either increased, in the same direction, the effect on gene expression or had no further effect. At low concentrations (0.2 nM TCDD and 1 μM α-endosulfan), the POPs still had significant effects and the levels of expression of the corresponding proteins were found to be affected for some genes. Particularly striking was the 80-90% inhibition, by the mixture, of the expression of a number of genes of several hepatic intermediary metabolic pathways (glycerolipid metabolism, FXR/RXR activation, glycolysis/gluconeogenesis, retinoid and bile acid biosynthesis), whereas each pollutant alone had only a moderate effect.

Published
2015
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