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1. Alternariol induces abnormal nuclear morphology and cell cycle arrest in murine RAW 264.7 macrophages

Author

Odile Sergent, James J. Pestka, Dominique Lagadic-Gossmann, Kaisa Haglund, Jørn A. Holme, Anita Solhaug, Béatrice Dendelé, Gunnar Sundstøl Eriksen, Le Corre, Morgane, Department of Chemistry and Toxicology, Norwegian Veterinary Institute [Oslo], Division of Environmental Medicine, Norwegian Institute of Public Health [Oslo] (NIPH), Department of Biochemistry, Institute for Cancer Research-The Norwegian Radium Hospital, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Stress, membrane et signalisation (SMS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Department of Food Science and Human Nutrition, Michigan State University [East Lansing], Michigan State University System-Michigan State University System, The work was supported by Research Council of Norway through the project: Toxicological characterization of selected secondary fungal metabolites in Norwegian grain. [Grant nr: 185622/V40]., Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes 1 (UR1)

Subjects
Cell cycle checkpoint, Alternariol, Cell Cycle Proteins, MESH: Microscopy, Fluorescence, MESH: Flow Cytometry, Toxicology, MESH: G2 Phase Cell Cycle Checkpoints, Lactones, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: Microscopy, Confocal, MESH: Animals, Cyclin B1, Topoisomerase IIα, 2. Zero hunger, 0303 health sciences, Microscopy, Confocal, MESH: M Phase Cell Cycle Checkpoints, MESH: Cell Nucleus Shape, General Medicine, Cell cycle, Flow Cytometry, G2 Phase Cell Cycle Checkpoints, Cell Nucleus Size, 030220 oncology & carcinogenesis, MESH: Microscopy, Electron, Transmission, MESH: Lactones, MESH: Cell Nucleus, Cell Nucleus Shape, Membrane Fluidity, MESH: Cell Nucleus Size, Blotting, Western, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Mycotoxins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Line, Polyploidy, 03 medical and health sciences, MESH: Cell Cycle Proteins, Microscopy, Electron, Transmission, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Polyploidy, Botany, Animals, MESH: Blotting, Western, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, Mitosis, 030304 developmental biology, Cell Nucleus, Macrophages, MESH: Macrophages, Mycotoxins, Molecular biology, MESH: Cell Line, Microscopy, Fluorescence, chemistry, Cytoplasm, Cell culture, M Phase Cell Cycle Checkpoints, MESH: Membrane Fluidity, Cytokinesis
Abstract

International audience; The mycotoxin alternariol (AOH), a frequent contaminant in fruit and cereal products, is known to induce DNA damage with subsequent cell cycle arrest. Here we elucidated the effects of AOH on stages of cell cycle progression using the RAW 264.7 macrophage model. AOH resulted in an accumulation of cells in the G2/M-phase (4N). Most cells exhibited a large G2 nucleus whereas numbers of true mitotic cells were reduced relative to control. Both cyclin B1 and p-cdc2 levels increased, while cyclin B1 remained in the cytoplasm; suggesting arrest in the G2/M transition point. Remarkably, after exposure to AOH for 24h, most of the cells exhibited abnormally shaped nuclei, as evidenced by partly divided nuclei, nuclear blebs, polyploidy and micronuclei (MN). AOH treatment also induced abnormal Aurora B bridges, suggesting that cytokinesis was interfered within cells undergoing karyokinesis. A minor part of the resultant G1 tetraploid (4N) cells re-entered the S-phase and progressed to 8N cells.

Published
2013
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2. Contents Vol. 29, 2012

Author

Yonggang Lu, Michael Reppel, Suozhu Shi, Nikolaus Blin, Louis Ruiz, Patricia R. M. Rocco, Pei Wang, Ting Zhang, Yicun Chen, Yamila V. Carmona Viglianco, Andreas Breß, Fanqin Zeng, Jaime Mas-Oliva, Soraia G. Abreu, Guibo Sun, Mingli Jin, Debora G. Xisto, Silke Haerteis, Carina Lammers, María Antonia Cid, Shefalee K. Bhavsar, Jun Zhang, Wolf-Michael Weber, Xueguang Zhang, Ilsley Colton, Yijin Luo, Tomoyuki Nishizaki, Enrique Jaimovich, Adriana L. Silva, Silvia del Valle Alonso, George Osol, Carlos Facundo Temprana, Verena Jendrossek, Hoo Kyun Choi, Shaoheng He, Zhihua Liu, Mu Li, Maurizio Mandalà, Yanfang Han, Henning Reis, Katja Steinke, Jochen Müller-Ehmsen, Marcelo M. Morales, Nadine Bangel-Ruland, Yvonne Knieper, David Mears, Odile Sergent, Lumian Zhang, Ana Cecilia Anzulovich, Tomo Saric, Xiaoyu Yu, Dan Yang, Nora Riveros, Dennis Rottländer, Xiaoning Zeng, Hitomi Kamiya, Min Cao, Theresa Dartsch, Xavier Tekpli, Lin Dou, Guiscard Seebohm, Ping Xie, Shuwen Liu, Heinrich Sticht, Yu Zheng, Ethel García-Latorre, Tanqi Lou, Kurt Pfannkuche, Zongfang Li, Ying He, María Antonia Martínez, Alicia Ortega, Dagoberto Delgado-Franco, Carlos A. Marra, Ximena Leighton, Daniel Schaal, Quan Hong, Haiwei Yang, Veronica A. Peotta, Ke Li, Carsten Zobel, Xu Zeng, Nathalie Strutz-Seebohm, Dominik Heider, Illani Atwater, Aldo Tirado-Cortes, Jessica Morgner, Guozhen Tan, Mathias C. Brandt, Jude S. Morton, Cui-Cui Li, Geraldine Leier, Xiaobo Sun, Guomin Ren, Tao Shen, Gang Hu, Eduardo Rojas, Miki Honda, Hannes Reuter, Claudine Irles, Stefan Brüschke, Yuansheng Xie, Gianna-Carina Gruen, Xiaoluan Liu, Jinhong Zheng, Jian Li, Charles L. Zimliki, Takeshi Kanno, Limei Zhang, Gonzalo Jorquera, Xiaofeng Le, Xiangmei Chen, Silvana S. Meyrelles, Dominique Lagadic-Gossmann, Jesús Vega-Moreno, Dong-Im Cho, R. Alvarez, Yong Man, Kurt Werner Schmid, Zohreh Hosseinzadeh, Suyun Ji, Ulrike Henrion, Sven Zumhagen, Zhidong Wang, Toni Schneider, Elisardo C. Vasquez, Kyeong-Man Kim, Akinobu Gotoh, Stephan Schwarzinger, Yang Lv, María Ángeles Trillo, Cui Li, Christoph Korbmacher, Magdalena Zak, ZunFu Ke, Ying Pan, Ae-Kyung Yi, Qing Guo, Simon Ockenpoehler, Birgit Stallmeyer, Kristian Schweimer, Marco Weiergraeber, Jørn A. Holme, Dario C. Ramirez, Katja Sobczak, Shu Wang, Rebecca M. Parodi-Rullán, Miguel Palacios-Sánchez, Yuanyuan Ji, Harvey B. Pollard, Meera Srivastava, Xun Liu, Julia Crosseti, Sabrina V. Martini, Hang Liu, Markus Pfister, Gabriel Peinkofer, Felix Brauer, Robert Rauh, Pablo Caviedes, Filomain Nguemo, Johnatas D. Silva, Jinzhi Wang, Shu Zhang, Marie-Thérèse Dimanche-Boitrel, Marlies Knipper, Laurence Huc, Rui Ding, Cheng Wang, José Casasnovas, Peter Ruth, Sandra T. Davidge, Jürgen Hescheler, Uta C. Hoppe, ZengChun Ye, Sandra E. Gomez-Mejiba, Nevenka Juretić, Alejandro Úbeda, Florian Lang, Paul Rösch, María Sofía Giménez, Can-Ming Li, So-Young Kim, Fengjun Wang, Mei Zheng, Xiuqing Huang, Niels Brandt, Mariela J. Coria, Li Zhang, Eric Schulze-Bahr, José Guzmán-Bárcenas, Giselle Barreto-Torres, Béatrice Dendelé, Manfred Watzele, Christoph Franz, Yumiko Fujita, Marcel Halbach, Joel Arias-Martínez, Daniel Kessler, Mirta Glassman, Sabzali Javadov, Takashi Nakano, and Ying Tang

Subjects
Physiology
Published
2012
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3. Protective action of n-3 fatty acids on benzo[a]pyrene-induced apoptosis through the plasma membrane remodeling-dependent NHE1 pathway

Author

Volker M. Arlt, Dominique Lagadic-Gossmann, Kévin Hardonnière, Béatrice Dendelé, Jørn A. Holme, Mallory Poët, Vincent Rioux, David H. Phillips, Daniel Catheline, Xavier Tekpli, Eszter Nagy, Laure Debure, Marie-Thérèse Dimanche-Boitrel, Steinar Øvrebø, Odile Sergent, Steen Mollerup, Martine Chevanne, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Stress, membrane et signalisation (SMS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Norwegian Institute of Public Health [Oslo] (NIPH), Récepteur de mort et échappement tumoral, Laboratoire de Biochimie et Nutrition Humaine, AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), King‘s College London, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), This study was financially supported by the Ligue Nationale contre le Cancer (FR) and Cancer Research UK., Cadieu, Muriel, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
eicosapentaenoic acid, Intracellular Space, Toxicology, chemistry.chemical_compound, 0302 clinical medicine, Cytochrome P-450 Enzyme System, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], chemistry.chemical_classification, lipid rafts, 0303 health sciences, Sodium-Hydrogen Exchanger 1, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, apoptosis, benzo[a]pyrene, General Medicine, Hydrogen-Ion Concentration, docosahexaenoic acid, Lipids, Eicosapentaenoic acid, Protein Transport, Cholesterol, Benzo(a)pyrene, Biochemistry, Docosahexaenoic acid, 030220 oncology & carcinogenesis, Saturated fatty acid, Benzopyrene, lipids (amino acids, peptides, and proteins), Docosapentaenoic acid, Signal Transduction, Polyunsaturated fatty acid, Sodium-Hydrogen Exchangers, Docosahexaenoic Acids, Protective Agents, Models, Biological, Cell Line, 03 medical and health sciences, Membrane Microdomains, Na+/H+ exchanger 1, Fatty Acids, Omega-3, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Cell Membrane, Metabolism, Rats, chemistry, Tumor Suppressor Protein p53, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, DNA Damage
Abstract

International audience; Plasma membrane is an early target of polycyclic aromatic hydrocarbons (PAH). We previously showed that the PAH prototype, benzo[a]pyrene (B[a]P), triggers apoptosis via DNA damage-induced p53 activation (genotoxic pathway) and via remodeling of the membrane cholesterol-rich microdomains called lipid rafts, leading to changes in pH homeostasis (non-genotoxic pathway). As omega-3 (n-3) fatty acids can affect membrane composition and function or hamper in vivo PAH genotoxicity, we hypothesized that addition of physiologically relevant levels of polyunsaturated n-3 fatty acids (PUFAs) might interfere with B[a]P-induced toxicity. The effects of two major PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were tested on B[a]P cytotoxicity in the liver epithelial cell line F258. Both PUFAs reduced B[a]P-induced apoptosis. Surprisingly, pre-treatment with DHA increased the formation of reactive B[a]P metabolites, resulting in higher levels of B[a]P-DNA adducts. EPA had no apparent effect on B[a]P metabolism or related DNA damage. EPA and DHA prevented B[a]P-induced apoptotic alkalinization by affecting Na(+)/H(+) exchanger 1 activity. Thus, the inhibitory effects of omega-3 fatty acids on B[a]P-induced apoptosis involve a non-genotoxic pathway associated with plasma membrane remodeling. Our results suggest that dietary omega-3 fatty acids may have marked effects on the biological consequences of PAH exposure.

Published
2014
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4. Mycotoxin-induced cell death and inflammatory responses in macrophages

Author

Anders Gammelsrud, Béatrice Dendelé, Anita Solhaug, Magne Refsnes, Rune Becher, Wiggo J. Sandberg, Jørn A. Holme, Dominique Lagadic-Gossmann, Gunnar Sundstøl Eriksen, Division of Environmental Medicine, Norwegian Institute of Public Health [Oslo] (NIPH), Department of Chemistry and Toxicology, Norwegian Veterinary Institute [Oslo], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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
chemistry.chemical_compound, Programmed cell death, chemistry, [SDV]Life Sciences [q-bio], Immunology, General Medicine, Biology, Toxicology, Mycotoxin, Macrophage inflammatory protein, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2012
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5. Enniatin B-induced cell death and inflammatory responses in RAW 267.4 murine macrophages

Author

Jørn A. Holme, L. Ivanova, A. Gammelsrud, Magne Refsnes, Rune Becher, Béatrice Dendelé, Dominique Lagadic-Gossmann, A. Kocbach Bolling, Wiggo J. Sandberg, Gunnar Sundstøl Eriksen, Anita Solhaug, Division of Environmental Medicine, Norwegian Institute of Public Health [Oslo] (NIPH), Department of Chemistry and Toxicology, Norwegian Veterinary Institute [Oslo], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Stress, membrane et signalisation (SMS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Le Corre, Morgane, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes 1 (UR1)

Subjects
MESH: Inflammation, MESH: Cell Death, Inflammasomes, MESH: Cathepsin B, Interleukin-1beta, Apoptosis, Toxicology, Cathepsin B, MESH: Cell Cycle Checkpoints, Inflammasome, Mice, 0302 clinical medicine, MESH: Inflammasomes, MESH: Interleukin-1beta, MESH: Caspase 1, Depsipeptides, Cytotoxic T cell, MESH: Animals, 0303 health sciences, Cell Death, Caspase 1, Cell Differentiation, Cell cycle, Cell biology, Biochemistry, 030220 oncology & carcinogenesis, MESH: Microscopy, Electron, Transmission, Cytokines, MESH: Cell Differentiation, Programmed cell death, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Line, 03 medical and health sciences, Microscopy, Electron, Transmission, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Cell Proliferation, Animals, MESH: Mice, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cell Proliferation, 030304 developmental biology, Inflammation, Pharmacology, Cathepsin, Enniatins, Macrophages, MESH: Apoptosis, Lymphokine, MESH: Macrophages, Cell Cycle Checkpoints, Mycotoxins, MESH: Depsipeptides, MESH: Cell Line, Cell culture, Lysosomes, MESH: Lysosomes
Abstract

International audience; The mycotoxin enniatin B (EnnB) is predominantly produced by species of the Fusarium genera, and often found in grain. The cytotoxic effect of EnnB has been suggested to be related to its ability to form ionophores in cell membranes. The present study examines the effects of EnnB on cell death, differentiation, proliferation and pro-inflammatory responses in the murine monocyte-macrophage cell line RAW 264.7. Exposure to EnnB for 24 h caused an accumulation of cells in the G0/G1-phase with a corresponding decrease in cyclin D1. This cell cycle-arrest was possibly also linked to the reduced cellular ability to capture and internalize receptors as illustrated by the lipid marker ganglioside GM1. EnnB also increased the number of apoptotic, early apoptotic and necrotic cells, as well as cells with elongated spindle-like morphology. The Neutral Red assay indicated that EnnB induced lysosomal damage; supported by transmission electron microscopy (TEM) showing accumulation of lipids inside the lysosomes forming lamellar structures/myelin bodies. Enhanced levels of activated caspase-1 were observed after EnnB exposure and the caspase-1 specific inhibitor ZYVAD-FMK reduced EnnB-induced apoptosis. Moreover, EnnB increased the release of interleukin-1 beta (IL-1β) in cells primed with lipopolysaccharide (LPS), and this response was reduced by both ZYVAD-FMK and the cathepsin B inhibitor CA-074Me. In conclusion, EnnB was found to induce cell cycle arrest, cell death and inflammation. Caspase-1 appeared to be involved in the apoptosis and release of IL-1β and possibly activation of the inflammasome through lysosomal damage and leakage of cathepsin B.

Published
2012
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6. Identification of the couple GSK3α/c-Myc as a new regulator of hexokinase II in benzo[a]pyrene-induced apoptosis

Author

Dominique Lagadic-Gossmann, Jørn A. Holme, Laurence Huc, Odile Sergent, Béatrice Dendelé, Xavier Tekpli, Marie-Thérèse Dimanche-Boitrel, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Stress, membrane et signalisation (SMS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Division of Environmental Medicine, Norwegian Institute of Public Health [Oslo] (NIPH), Ligue Nationale contre le Cancer, Holme, JA, Huc-Lemarié, Laurence, Lagadic-Gossmann, D, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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
Cell, Apoptosis, Mitochondrion, Biology, Toxicology, GSK3, Cell Line, Proto-Oncogene Proteins c-myc, Glycogen Synthase Kinase 3, 03 medical and health sciences, 0302 clinical medicine, GSK-3, Hexokinase, Benzo(a)pyrene, medicine, Animals, GSK3B, Carcinogen, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Reactive oxygen species, Glycogen Synthase Kinase 3 beta, Intrinsic apoptosis, Hexokinase II, c-Myc, Mitochondria, Benzo[a]pyrene, NHE1, GLYCOGEN-SYNTHASE KINASE-3, DEPENDENT ANION CHANNEL, C-MYC, HEPATOCELLULAR-CARCINOMA, SIGNALING PATHWAYS, PRESSURE-OVERLOAD, ENERGY-METABOLISM, CELL-DEATH, KAPPA-B, INHIBITION, General Medicine, Rats, Cell biology, medicine.anatomical_structure, chemistry, 13. Climate action, 030220 oncology & carcinogenesis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Carcinogens, Environmental Pollutants
Abstract

International audience; The early apoptotic events induced by environmental pollutants with carcinogenic properties are poorly understood. Here, we focus on the early cytotoxic effects of benzo[a]pyrene (B[a]P). In F258 rat hepatic epithelial cells, B[a]P induces intrinsic apoptosis via a mitochondrial dysfunction characterized by the release of hexokinase II (HKII) from the mitochondria. Cancer cells often have an anomalous cell energy metabolism; since HKII dysfunction regulates B[a]P-induced apoptosis in F258 cells, but may also alter cell energy metabolism, HKII release from the mitochondria may represent an important B[a]P-related carcinogenic issue. Thus in the present study, we aimed at deciphering the mechanisms underlying HKII dysfunction upon B[a]P exposure. We show that while glycogen synthase kinase 3 beta (GSK3β) regulated the expression of HKII at the transcriptional level, glycogen synthase kinase 3 alpha (GSK3α) was involved in B[a]P-induced apoptosis via a decrease in c-Myc expression. The reduced level of c-Myc caused the relocation of HKII from the mitochondria to the cytosol, thereby being involved in the formation of reactive oxygen species and apoptosis. In conclusion, we show that the couple GSK3α/c-Myc plays a key role in B[a]P-induced early apoptotic cell signaling via HKII dysfunction.

Published
2012
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7. NHE-1 relocation outside cholesterol-rich membrane microdomains is associated with its benzo[a]pyrene-related apoptotic function

Author

Dominique Lagadic-Gossmann, Odile Sergent, Béatrice Dendelé, Marie-Thérèse Dimanche-Boitrel, Xavier Tekpli, Jørn A. Holme, Laurence Huc, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Stress, membrane et signalisation (SMS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Division of Environmental Medicine, Norwegian Institute of Public Health [Oslo] (NIPH), Ligue Nationale contre le Cancer, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Le Corre, Morgane, Holme, JA, and Lagadic-Gossmann , D

Subjects
Programmed cell death, MESH: Protein Transport, Sodium-Hydrogen Exchangers, Calmodulin, MESH: Rats, Physiology, Immunoprecipitation, Intracellular pH, Blotting, Western, NHE-1, Cholesterol-rich-microdomains, Apoptosis, Benzo[a]pyrene, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MESH: Cholesterol, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Benzo(a)pyrene, Benzo(a)pyrene, Animals, MESH: Blotting, Western, MESH: Animals, 030304 developmental biology, 0303 health sciences, MESH: Sodium-Hydrogen Antiporter, biology, MESH: Apoptosis, SODIUM-HYDROGEN EXCHANGE, POLYCYCLIC AROMATIC-HYDROCARBONS, SMOOTH-MUSCLE-CELLS, NA+/H+ EXCHANGER, LIPID RAFTS, INTRACELLULAR PH, JANUS KINASE-2, ACTIVATION, EXPRESSION, PROTEIN, MESH: Calmodulin, Transport protein, Cell biology, Rats, MESH: Cell Line, Protein Transport, Membrane, Cholesterol, chemistry, 13. Climate action, 030220 oncology & carcinogenesis, biology.protein
Abstract

International audience; BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are ubiquitous toxic environmental pollutants capable of inducing cell death. Intracellular pH plays a key role in the regulation of cell survival and death. Our previous works have demonstrated that intracellular alkalinization mediated by Na(+)/H(+) exchanger 1 (NHE-1) is a critical event involved in B[a]P-induced apoptosis. The aim of this study was to further elucidate the mechanisms of NHE-1 activation upon B[a]P exposure. METHODS: We tested the effects of plasma membrane cholesterol enrichment or depletion on B[a]P-induced NHE-1 activation related to apoptosis. We isolated cholesterol-rich plasma membrane microdomains to assess NHE-1 submembrane location and immunoprecipitated NHE-1 from the different sub-membrane fractions obtained to examine NHE-1 protein interactions during B[a]P-induced apoptosis. RESULTS: We found that NHE-1 is preferentially located in cholesterol-rich microdomains and that B[a]P activates NHE-1 via its relocation and binding of calmodulin outside these specialized plasma membrane microstructures; these events are necessary for the execution of the apoptosis-related intracellular alkalinization. CONCLUSION: Plasma membrane location of NHE-1 affects its protein interactions and apoptotic function.

Published
2012
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8. Effects of the omega-3 DHA and EPA on benzo[a]pyrene-induced apoptosis in liver epithelial cells

Author

Volker M. Arlt, Eszter Nagy, Béatrice Dendelé, Xavier Tekpli, Dominique Lagadic-Gossmann, Jørn A. Holme, Odile Sergent, Steinar Øvrebø, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), King‘s College London, Division of Environmental Medicine, Norwegian Institute of Public Health [Oslo] (NIPH), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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
0303 health sciences, [SDV]Life Sciences [q-bio], General Medicine, Toxicology, Omega, Molecular biology, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Benzo(a)pyrene, chemistry, Apoptosis, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2011
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9. Alternariol-induced ROS causes DNA damage and accumulation in the G2/M transition

Author

Dominique Lagadic-Gossmann, Anita Solhaug, James J. Pestka, Jørn A. Holme, Béatrice Dendelé, Gunnar Sundstøl Eriksen, Kaisa Haglund, Bjørn Spilsberg, Laura L. Vines, Department of Chemistry and Toxicology, Norwegian Veterinary Institute [Oslo], Division of Environmental Medicine, Norwegian Institute of Public Health [Oslo] (NIPH), Department of Food Science and Human Nutrition, Michigan State University [East Lansing], Michigan State University System-Michigan State University System, Department of Biochemistry, Institute for Cancer Research-The Norwegian Radium Hospital, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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
0303 health sciences, Chemistry, DNA damage, [SDV]Life Sciences [q-bio], Alternariol, General Medicine, Toxicology, Molecular biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, G2/M Transition, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

International audience

Published
2012
Full Text
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