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1. Exploration of microRNAs from blood extracellular vesicles as biomarkers of exposure to polycyclic aromatic hydrocarbons

Author: Jérémy Amossé, Rima Souki, Maguy El Hajjar, Marie Marques, Valentine Genêt, Alexis Février, Morgane Le Gall, Benjamin SaintPierre, Franck Letourneur, Eric Le Ferrec, Dominique Lagadic-Gossmann, Christine Demeilliers, and Lydie Sparfel
Subjects: benzo(a)pyrene, extracellular vesicles, microRNAs, biomarkers, exposure, Environmental pollution, TD172-193.5, Environmental sciences, GE1-350
Abstract: Exposure to polycyclic aromatic hydrocarbons (PAHs), ubiquitously environmental contaminant, leads to the development of major toxic effects on human health, such as carcinogenic and immunosuppressive alterations reported for the most studied PAH, i.e., benzo(a)pyrene (B(a)P). In order to assess the risk associated with this exposure, it is necessary to have predictive biomarkers. Thus, extracellular vesicles (EVs) and their microRNA (miRNA) contents, have recently been proposed as potentially interesting biomarkers in Toxicology. Our study here explores the use of vesicles secreted and found in blood fluids, and their miRNAs, as biomarkers of exposure to B(a)P alone and within a realistic occupational mixture. We isolated EVs from primary human cultured blood mononuclear cells (PBMCs) and rat plasma after PAH exposure and reported an increased EV production by B(a)P, used either alone or in the mixture, in vitro and in vivo. We then investigated the association of this EV release with the blood concentration of the 7,8,9,10-hydroxy (tetrol)-B(a)P reactive metabolite, in rats. By performing RNA-sequencing (RNA-seq) of miRNAs in PBMC-derived EVs, we analyzed miRNA profiles and demonstrated the regulation of the expression of miR-342–3p upon B(a)P exposure. We then validated B(a)P-induced changes of miR-342–3p expression in vivo in rat plasma-derived EVs. Overall, our study highlights the feasibility of using EVs and their miRNA contents, as biomarkers of PAH exposure and discusses their potential in environmental Toxicology.
Published: 2024
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2. A New In Vivo Zebrafish Bioassay Evaluating Liver Steatosis Identifies DDE as a Steatogenic Endocrine Disruptor, Partly through SCD1 Regulation

Author: Hélène Le Mentec, Emmanuelle Monniez, Antoine Legrand, Céline Monvoisin, Dominique Lagadic-Gossmann, and Normand Podechard
Subjects: zebrafish larvae, bioassay, endocrine disruptor compounds, NAFLD, liver steatosis, DDE, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Non-alcoholic fatty liver disease (NAFLD), which starts with liver steatosis, is a growing worldwide epidemic responsible for chronic liver diseases. Among its risk factors, exposure to environmental contaminants, such as endocrine disrupting compounds (EDC), has been recently emphasized. Given this important public health concern, regulation agencies need novel simple and fast biological tests to evaluate chemical risks. In this context, we developed a new in vivo bioassay called StAZ (Steatogenic Assay on Zebrafish) using an alternative model to animal experimentation, the zebrafish larva, to screen EDCs for their steatogenic properties. Taking advantage of the transparency of zebrafish larvae, we established a method based on fluorescent staining with Nile red to estimate liver lipid content. Following testing of known steatogenic molecules, 10 EDCs suspected to induce metabolic disorders were screened and DDE, the main metabolite of the insecticide DDT, was identified as a potent inducer of steatosis. To confirm this and optimize the assay, we used it in a transgenic zebrafish line expressing a blue fluorescent liver protein reporter. To obtain insight into DDE’s effect, the expression of several genes related to steatosis was analyzed; an up-regulation of scd1 expression, probably relying on PXR activation, was found, partly responsible for both membrane remodeling and steatosis.
Published: 2023
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3. Lipophilic components of diesel exhaust particles induce pro-inflammatory responses in human endothelial cells through AhR dependent pathway(s)

Author: Bendik C. Brinchmann, Tonje Skuland, Mia H. Rambøl, Krisztina Szoke, Jan E. Brinchmann, Arno C. Gutleb, Elisa Moschini, Alena Kubátová, Klara Kukowski, Eric Le Ferrec, Dominique Lagadic-Gossmann, Per E. Schwarze, Marit Låg, Magne Refsnes, Johan Øvrevik, and Jørn A. Holme
Subjects: Air pollution, Diesel exhaust particles, Inflammation, Cardiovascular disease, Atherosclerosis, Endothelial cells, Toxicology. Poisons, RA1190-1270, Industrial hygiene. Industrial welfare, HD7260-7780.8
Abstract: Abstract Background Exposure to traffic-derived particulate matter (PM), such as diesel exhaust particles (DEP), is a leading environmental cause of cardiovascular disease (CVD), and may contribute to endothelial dysfunction and development of atherosclerosis. It is still debated how DEP and other inhaled PM can contribute to CVD. However, organic chemicals (OC) adhered to the particle surface, are considered central to many of the biological effects. In the present study, we have explored the ability of OC from DEP to reach the endothelium and trigger pro-inflammatory reactions, a central step on the path to atherosclerosis. Results Exposure-relevant concentrations of DEP (0.12 μg/cm2) applied on the epithelial side of an alveolar 3D tri-culture, rapidly induced pro-inflammatory and aryl hydrocarbon receptor (AhR)-regulated genes in the basolateral endothelial cells. These effects seem to be due to soluble lipophilic constituents rather than particle translocation. Extractable organic material of DEP (DEP-EOM) was next fractionated with increasing polarity, chemically characterized, and examined for direct effects on pro-inflammatory and AhR-regulated genes in human microvascular endothelial (HMEC-1) cells and primary human endothelial cells (PHEC) from four healthy donors. Exposure-relevant concentrations of lipophilic DEP-EOM (0.15 μg/cm2) induced low to moderate increases in IL-1α, IL-1β, COX2 and MMP-1 gene expression, and the MMP-1 secretion was increased. By contrast, the more polar EOM had negligible effects, even at higher concentrations. Use of pharmacological inhibitors indicated that AhR and protease-activated receptor-2 (PAR-2) were central in regulation of EOM-induced gene expression. Some effects also seemed to be attributed to redox-responses, at least at the highest exposure concentrations tested. Although the most lipophilic EOM, that contained the majority of PAHs and aliphatics, had the clearest low-concentration effects, there was no straight-forward link between chemical composition and biological effects. Conclusion Lipophilic and semi-lipophilic chemicals seemed to detach from DEP, translocate through alveolar epithelial cells and trigger pro-inflammatory reactions in endothelial cells at exposure-relevant concentrations. These effects appeared to be triggered by AhR agonists, and involve PAR-2 signaling.
Published: 2018
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4. Benzo(a)pyrene triggers desensitization of β2-adrenergic pathway

Author: Abdullah Mayati, Normand Podechard, Manuelle Rineau, Lydie Sparfel, Dominique Lagadic-Gossmann, Olivier Fardel, and Eric Le Ferrec
Subjects: Medicine, Science
Abstract: Abstract Exposure to environmental polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene (B(a)P), has been linked to several health-threatening risks. PAHs were also shown to hinder adrenergic receptor (ADR) responses. As we previously demonstrated that B(a)P can directly interact with the β2ADR, we investigated here whether B(a)P could decrease β2ADR responsiveness by triggering receptor desensitization phenomena. We firstly showed that exposure to B(a)P reduced β2ADR-mediated epinephrine-induced induction of NR4A gene mRNAs and of intracellular cAMP. Analysis of β2ADR protein expression demonstrated that B(a)P rapidly decreased membrane expression of β2ADR with a subsequent degradation of receptor protein. B(a)P exposure concomitantly rapidly increased the β2ADR mRNA levels. The use of the β-blockers, propranolol and ICI 118.551, demonstrated the involvement of β2ADR itself in this increase. However, sustained exposure to B(a)P induced a diminution of β2ADR mRNA steady-state as a result of the acceleration of its degradation. Together, these results show that, beside the well-known activation of the aryl hydrocarbon receptor, PAH deleterious effects may involve the dysfunction of adrenergic responses through, in part, the desensitization of β2ADR. This may be taken in consideration when β2-agonists/antagonists are administered in patients exposed to important concentrations of PAHs, e.g. in cigarette smokers.
Published: 2017
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5. Role for the ATPase inhibitory factor 1 in the environmental carcinogen-induced Warburg phenotype

Author: Kévin Hardonnière, Morgane Fernier, Isabelle Gallais, Baharia Mograbi, Normand Podechard, Eric Le Ferrec, Nathalie Grova, Brice Appenzeller, Agnès Burel, Martine Chevanne, Odile Sergent, Laurence Huc, Sylvie Bortoli, and Dominique Lagadic-Gossmann
Subjects: Medicine, Science
Abstract: Abstract Most tumors undergo metabolic reprogramming towards glycolysis, the so-called Warburg effect, to support growth and survival. Overexpression of IF1, the physiological inhibitor of the F0F1ATPase, has been related to this phenomenon and appears to be a relevant marker in cancer. Environmental contributions to cancer development are now widely accepted but little is known about the underlying intracellular mechanisms. Among the environmental pollutants humans are commonly exposed to, benzo[a]pyrene (B[a]P), the prototype molecule of polycyclic aromatic hydrocarbons (PAHs), is a well-known human carcinogen. Besides apoptotic signals, B[a]P can also induce survival signals in liver cells, both likely involved in cancer promotion. Our previous works showed that B[a]P elicited a Warburg-like effect, thus favoring cell survival. The present study aimed at further elucidating the molecular mechanisms involved in the B[a]P-induced metabolic reprogramming, by testing the possible involvement of IF1. We presently demonstrate, both in vitro and in vivo, that PAHs, especially B[a]P, strongly increase IF1 expression. Such an increase, which might rely on β2-adrenergic receptor activation, notably participates to the B[a]P-induced glycolytic shift and cell survival in liver cells. By identifying IF1 as a target of PAHs, this study provides new insights about how environmental factors may contribute to related carcinogenesis.
Published: 2017
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6. Lipophilic Chemicals from Diesel Exhaust Particles Trigger Calcium Response in Human Endothelial Cells via Aryl Hydrocarbon Receptor Non-Genomic Signalling

Author: Bendik C. Brinchmann, Eric Le Ferrec, Normand Podechard, Dominique Lagadic-Gossmann, Kenji F. Shoji, Aubin Penna, Klara Kukowski, Alena Kubátová, Jørn A. Holme, and Johan Øvrevik
Subjects: diesel exhaust particle extracts, endothelial cells, calcium signalling, membrane microdomains, aryl hydrocarbon receptor, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Exposure to diesel exhaust particles (DEPs) affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca2+]i is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM) on [Ca2+]i and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with n-hexane (n-Hex-EOM), dichloromethane (DCM-EOM), methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the n-Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in n-Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1) using micro-spectrofluorometry. The lipophilic n-Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca2+]i increases in HMEC-1. n-Hex-EOM triggered [Ca2+]i increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE). By contrast, the less lipophilic DCM-EOM triggered [Ca2+]i increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE). Both extracts increased [Ca2+]i via aryl hydrocarbon receptor (AhR) non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca2+]i increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by n-hexane and DCM seem to induce rapid AhR-dependent [Ca2+]i increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction extracted by DCM also caused an AhR-dependent reduction in global membrane order, which appeared to be connected to the [Ca2+]i increase.
Published: 2018
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7. RNAi-based screening identifies kinases interfering with dioxin-mediated up-regulation of CYP1A1 activity.

Author: David Gilot, Nolwenn Le Meur, Fanny Giudicelli, Marc Le Vée, Dominique Lagadic-Gossmann, Nathalie Théret, and Olivier Fardel
Subjects: Medicine, Science
Abstract: The aryl hydrocarbon receptor (AhR) is a transcription factor activated by several environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and involved in carcinogenesis and various physiological processes, including immune response and endocrine functions. Characterization of kinases-related AhR transduction pathway remains an important purpose.We performed a kinome-wide siRNA screen in human mammary MCF-7 cells to identify non redundant protein kinases implicated in the up-regulation of cytochrome P-450 (CYP) 1A1 activity, an AhR referent target, in response to TCDD exposure. To this aim, we monitored CYP1A1-related ethoxyresorufin-O-deethylase (EROD) activity and quantified cell density. This normalization was crucial since it allowed us to focus only on siRNA affecting EROD activity and discard siRNA affecting cell density. Analyses of the cell density data allowed us to identify several hits already well-characterized as effectors of the cell cycle and original hits. Collectively, these data fully validated the protocol and the siRNA library. Next, 22 novel candidates were identified as kinases potentially implicated in the up-regulation of CYP1A1 in response to TCDD, without alteration of cell survival or cell proliferation. The siRNA library screen gave a limited number of hits (approximately 3%). Interestingly, four of them are able to bind calmodulin among which the IP3 kinase A (ITPKA) and pregnancy up-regulated non-ubiquitously expressed CaM kinase (PNCK, also named CaMKIβ). Remarkably, for both proteins, their kinase activity depends on the calmodulin binding. Involvement of ITPKA and PNCK in TCDD-mediated CYP1A1 up-regulation was further validated by screening-independent expression knock-down. PNCK was finally shown to regulate activation of CaMKIα, a CaMKI isoform previously reported to interplay with the AhR pathway.These data fully support a role for both IP3-related kinase and CaMK isoforms in the AhR signaling cascade. More generally, this study also highlights the interest of large scale loss-of-function screens for characterizing the molecular mechanism of action of environmental contaminants.
Published: 2011
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8. Data from c-Jun NH2-Terminal Kinase–Related Na+/H+ Exchanger Isoform 1 Activation Controls Hexokinase II Expression in Benzo(a)Pyrene-Induced Apoptosis

Author: Dominique Lagadic-Gossmann, Marie-Thérèse Dimanche-Boitrel, Morgane Gorria, Gwénaelle Le Moigne, Claire Gardyn, Anita Solhaug, Mary Rissel, Jørn A. Holme, Xavier Tekpli, and Laurence Huc
Abstract: Regulation of the balance between survival, proliferation, and apoptosis on carcinogenic polycyclic aromatic hydrocarbon (PAH) exposure is still poorly understood and more particularly the role of physiologic variables, including intracellular pH (pHi). Although the involvement of the ubiquitous pHi regulator Na+/H+ exchanger isoform 1 (NHE1) in tumorigenesis is well documented, less is known about its role and regulation during apoptosis. Our previous works have shown the primordial role of NHE1 in carcinogenic PAH-induced apoptosis. This alkalinizing transporter was activated by an early CYP1-dependent H2O2 production, subsequently promoting mitochondrial dysfunction leading to apoptosis. The aim of this study was to further elucidate how NHE1 was activated by benzo(a)pyrene (BaP) and what the downstream events were in the context of apoptosis. Our results indicate that the mitogen-activated protein kinase kinase 4/c-Jun NH2-terminal kinase (MKK4/JNK) pathway was a link between BaP-induced H2O2 production and NHE1 activation. This activation, in combination with BaP-induced phosphorylated p53, promoted mitochondrial superoxide anion production, supporting the existence of a common target for NHE1 and p53. Furthermore, we showed that the mitochondrial expression of glycolytic enzyme hexokinase II (HKII) was decreased following a combined action of NHE1 and p53 pathways, thereby enhancing the BaP-induced apoptosis. Taken together, our findings suggest that, on BaP exposure, MKK4/JNK targets NHE1 with consequences on HKII protein, which might thus be a key protein during carcinogenic PAH apoptosis. [Cancer Res 2007;67(4):1696–705]
Published: 2023

9. Supplementary Methods from c-Jun NH2-Terminal Kinase–Related Na+/H+ Exchanger Isoform 1 Activation Controls Hexokinase II Expression in Benzo(a)Pyrene-Induced Apoptosis

Author: Dominique Lagadic-Gossmann, Marie-Thérèse Dimanche-Boitrel, Morgane Gorria, Gwénaelle Le Moigne, Claire Gardyn, Anita Solhaug, Mary Rissel, Jørn A. Holme, Xavier Tekpli, and Laurence Huc
Abstract: Supplementary Methods from c-Jun NH2-Terminal Kinase–Related Na+/H+ Exchanger Isoform 1 Activation Controls Hexokinase II Expression in Benzo(a)Pyrene-Induced Apoptosis
Published: 2023

10. Supplementary Figures 1-4, Methods from Nongenomic Effects of Cisplatin: Acute Inhibition of Mechanosensitive Transporters and Channels without Actin Remodeling

Author: Mallorie Poët, Laurent Counillon, Michel Tauc, Cyril Rauch, Marie Thérèse Dimanche-Boitrel, Dominique Lagadic-Gossmann, Pierre Gounon, Pierre Henri Puech, Nadir Djerbi, Christophe Duranton, and Nina Milosavljevic
Abstract: Supplementary Figures 1-4, Methods from Nongenomic Effects of Cisplatin: Acute Inhibition of Mechanosensitive Transporters and Channels without Actin Remodeling
Published: 2023

11. Supplementary Materials from Cisplatin-Induced Apoptosis Involves Membrane Fluidification via Inhibition of NHE1 in Human Colon Cancer Cells

Author: Marie-Thérèse Dimanche-Boitrel, Dominique Lagadic-Gossmann, Erich Gulbins, Laurent Counillon, Bernd Kaina, Markus Christmann, Martine Chevanne, Morgane Gorria, Laurent Vernhet, Gwenaëlle LeMoigne-Muller, Odile Sergent, Olivier Meurette, Xavier Tekpli, and Amélie Rebillard
Abstract: Supplementary Materials from Cisplatin-Induced Apoptosis Involves Membrane Fluidification via Inhibition of NHE1 in Human Colon Cancer Cells
Published: 2023

12. Small RNA-sequencing reveals the involvement of microRNA-132 in benzo[a]pyrene-induced toxicity in primary human blood cells

Author: Rima Souki, Jérémy Amosse, Valentine Genêt, Morgane Le Gall, Benjamin Saintpierre, Franck Letourneur, Anne Maître, Christine Demeilliers, Eric Le Ferrec, Dominique Lagadic-Gossmann, Normand Podechard, Lydie Sparfel, 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Environnement et Prévention en Santé des Populations (TIMC-EPSP ), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), and The funding of this work was supported by The French National Research Program for Environmental and Occupational Health of Anses (2019/1/010) Rima Souki had a doctoral fellowship from the French Ministry for Higher Education and Research. Jeremy Amosse was a post-doctoral recipient from Anses. We are also thankful to the faculty of Pharmacy of Rennes, for funding the extended contract of Rima Souki.
Subjects: Benzo[a]pyrene, Cytochromes P-450 1A1 and 1B1, Peripheral blood mononuclear cells, [SDV]Life Sciences [q-bio], Health, Toxicology and Mutagenesis, miR-132–3p, [SDE]Environmental Sciences, General Medicine, Toxicology, Pollution, Aryl hydrocarbon receptor, Polycyclic aromatic hydrocarbons, microRNAs
Abstract: International audience; Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental contaminants, triggering deleterious effects such as carcinogenicity and immunosuppression, and peripheral blood mononuclear cells (PBMCs) are among the main cell types targeted by these pollutants. In the present study, we sought to identify the expression profiles and function of miRNAs, gene regulators involved in major cellular processes recently linked to environmental pollutants, in PBMC-exposed to the prototypical PAH, benzo[a]pyrene (B[a]P). Using small RNA deep sequencing, we identified several B[a]P-responsive miRNAs. Bioinformatics analyses showed that their predicted targets could modulate biological processes relevant to cell death and survival. Further studies of the most highly induced miRNA, miR-132, showed that its up-regulation by B[a]P was time- and dose-dependent and required aryl hydrocarbon receptor (AhR) activation. By evaluating the role of miR-132 in B[a]P-induced cell death, we propose a mechanism linking B[a]P-induced miR-132 expression and cytochromes P-450 (CYPs) 1A1 and 1B1 mRNA levels, which could contribute to the apoptotic response of PBMCs. Altogether, this study increases our understanding of the roles of miRNAs induced by B[a]P and provides the basis for further investigations into the mechanisms of gene expression regulation by PAHs.
Published: 2023

13. Combinatorial pathway disruption is a powerful approach to delineate metabolic impacts of endocrine disruptors

Author: Kévin Bernal, Charbel Touma, Chedi Erradhouani, Talía Boronat‐Belda, Lucas Gaillard, Sara Al Kassir, Hélène Le Mentec, Corinne Martin‐Chouly, Normand Podechard, Dominique Lagadic‐Gossmann, Sophie Langouet, François Brion, Anja Knoll‐Gellida, Patrick J. Babin, Iva Sovadinova, Pavel Babica, Karine Andreau, Robert Barouki, Jan Vondracek, Paloma Alonso‐Magdalena, Etienne Blanc, Min Ji Kim, Xavier Coumoul, 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 Paris Cité (UPCité), 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 ), Institut National de l'Environnement Industriel et des Risques - INERIS (FRANCE), Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III [Madrid] (ISC), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Univ Rennes, Inserm, EHESP, Irset, UMR S1085, Masaryk University [Brno] (MUNI), Institute of Biophysics of the Czech Academy of Sciences (IBP / CAS), Czech Academy of Sciences [Prague] (CAS), 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 ), Institut National de l'Environnement Industriel et des Risques (INERIS), The authors would like to thank the OBERON project (https://oberon-4eu.com/), funded by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 825712, INSERM, Université Paris Cité and INERIS. IS and PB thank the RECETOX Research Infrastructure (no. LM2018121) and the CETOCOEN EXCELLENCE project (no. CZ.02.1.01/0.0/0.0/17_043/0009632) financed by the Ministry of Education, Youth and Sports for supportive background. This work was supported from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 857560., European Project: 825712,H2020-EU.3.1.1. - Understanding health, wellbeing and disease,H2020-SC1-2018-Single-Stage-RTD,OBERON(2019), Jonchère, Laurent, and An integrative strategy of testing systems for identification of EDs related to metabolic disorders - OBERON - - H2020-EU.3.1.1. - Understanding health, wellbeing and disease2019-01-01 - 2019-12-31 - 825712 - VALID
Subjects: phthalate, perfluorinated compounds, [SDV]Life Sciences [q-bio], Biophysics, Cell Biology, dioxin, Biochemistry, appetite, bisphenol, inflammation, insulin resistance, microbiota, TBT, [SDV] Life Sciences [q-bio], Structural Biology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Genetics, Molecular Biology
Abstract: International audience; The prevalence of metabolic diseases, such as obesity, diabetes, metabolic syndrome and chronic liver diseases among others, has been rising for several years. Epidemiology and mechanistic (in vivo, in vitro and in silico) toxicology have recently provided compelling evidence implicating the chemical environment in the pathogenesis of these diseases. In this review, we will describe the biological processes that contribute to the development of metabolic diseases targeted by metabolic disruptors, and will propose an integrated pathophysiological vision of their effects on several organs. With regard to these pathomechanisms, we will discuss the needs, and the stakes of evolving the testing and assessment of endocrine disruptors to improve the prevention and management of metabolic diseases that have become a global epidemic since the end of last century.
Published: 2022

14. Corrigendum to 'Obesity III: Obesogen assays: Limitations, strengths, and new directions' [Biochem. Pharmacol. 199 (2022) 115014]

Author: Christopher D. Kassotis, Frederick S. vom Saal, Patrick J. Babin, Dominique Lagadic- Gossmann, Helene Le Mentec, Bruce Blumberg, Nicole Mohajer, Antoine Legrand, Vesna Munic Kos, Corinne Martin-Chouly, Normand Podechard, Sophie Langouët, Charbel Touma, Robert Barouki, Min Ji Kim, Karine Audouze, Mahua Choudhury, Nitya Shree, Amita Bansal, Sarah Howard, and Jerrold J. Heindel
Subjects: Pharmacology, Mice, Adipogenesis, 3T3-L1 Cells, Adipocytes, Animals, Cell Differentiation, Obesity, Caenorhabditis elegans, Biochemistry, Article, Zebrafish
Abstract: There is increasing evidence of a role for environmental contaminants in disrupting metabolic health in both humans and animals. Despite a growing need for well-understood models for evaluating adipogenic and potential obesogenic contaminants, there has been a reliance on decades-old in vitro models that have not been appropriately managed by cell line providers. There has been a quick rise in available in vitro models in the last ten years, including commercial availability of human mesenchymal stem cell and preadipocyte models; these models require more comprehensive validation but demonstrate real promise in improved translation to human metabolic health. There is also progress in developing three-dimensional and co-culture techniques that allow for the interrogation of a more physiologically relevant state. While diverse rodent models exist for evaluating putative obesogenic and/or adipogenic chemicals in a physiologically relevant context, increasing capabilities have been identified for alternative model organisms such as Drosophila, C. elegans, zebrafish, and medaka in metabolic health testing. These models have several appreciable advantages, including most notably their size, rapid development, large brood sizes, and ease of high-resolution lipid accumulation imaging throughout the organisms. They are anticipated to expand the capabilities of metabolic health research, particularly when coupled with emerging obesogen evaluation techniques as described herein.
Published: 2022

15. Transcriptomic analysis in zebrafish larvae identifies iron-dependent mitochondrial dysfunction as a possible key event of NAFLD progression induced by benzo[a]pyrene/ethanol co-exposure

Author: Muhammad Imran, Frédéric Chalmel, Odile Sergent, Bertrand Evrard, Hélène Le Mentec, Antoine Legrand, Aurélien Dupont, Maëlle Bescher, Simon Bucher, Bernard Fromenty, Laurence Huc, Lydie Sparfel, Dominique Lagadic-Gossmann, Normand Podechard, EHESP-Irset (EHESP-Irset), École des Hautes Études en Santé Publique [EHESP] (EHESP), Iqra University, 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 ), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Contaminants & Stress Cellulaire (ToxAlim-COMICS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), ANR-13-CESA-0009/Agence Nationale de la Recherchen°17CE040_00/Institut Thématique Multi-Organisme Cancer (ITMO Cancer) d'Aviesan, ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique(2013), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), LESUR, Hélène, and Contaminants et Environnements : Santé, Adaptabilité, Comportements et Usages - Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique - - STEATOX2013 - ANR-13-CESA-0009 - CESA - VALID
Subjects: Ethanol, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], AhR, B[a]P, Cell Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Toxicology, [SDV] Life Sciences [q-bio], [SDV.TOX] Life Sciences [q-bio]/Toxicology, Iron homeostasis, NAFLD, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Mitochondrial dysfunction, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Zebrafish
Abstract: International audience; Non-alcoholic fatty liver disease (NAFLD) is a worldwide epidemic for which environmental contaminants are increasingly recognized as important etiological factors. Among them, the combination of benzo[a]pyrene (B[a]P), a potent environmental carcinogen, with ethanol, was shown to induce the transition of steatosis toward steatohepatitis. However, the underlying mechanisms involved remain to be deciphered. In this context, we used high-fat diet fed zebrafish model, in which we previously observed progression of steatosis to a steatohepatitis-like state following a 7-day-co-exposure to 43 mM ethanol and 25 nM B[a]P. Transcriptomic analysis highlighted the potent role of mitochondrial dysfunction, alterations in heme and iron homeostasis, involvement of aryl hydrocarbon receptor (AhR) signaling, and oxidative stress. Most of these mRNA dysregulations were validated by RT-qPCR. Moreover, similar changes were observed using a human in vitro hepatocyte model, HepaRG cells. The mitochondria structural and functional alterations were confirmed by transmission electronic microscopy and Seahorse technology, respectively. Involvement of AhR signaling was evidenced by using in vivo an AhR antagonist, CH223191, and in vitro in AhR-knock-out HepaRG cells. Furthermore, as co-exposure was found to increase the levels of both heme and hemin, we investigated if mitochondrial iron could induce oxidative stress. We found that mitochondrial labile iron content was raised in toxicant-exposed larvae. This increase was prevented by the iron chelator, deferoxamine, which also inhibited liver co-exposure toxicity. Overall, these results suggest that the increase in mitochondrial iron content induced by B[a]P/ethanol co-exposure causes mitochondrial dysfunction that contributes to the pathological progression of NAFLD.
Published: 2022

16. Extracellular vesicles released by polycyclic aromatic hydrocarbons-treated hepatocytes trigger oxidative stress in recipient hepatocytes by delivering iron

Author: Nettie van Meteren, Odile Sergent, Dimitri Gobart, Isabelle Gallais, Dominique Lagadic-Gossmann, Eric Le Ferrec, Aurélien Dupont, Martine Chevanne, Aurore Collin, Fabienne Gauffre, Soizic Chevance, Agnès Burel, Ludivine Rault, Normand Podechard, 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 ), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Synthèse Caractérisation Analyse de la Matière (ScanMAT), Université de Rennes (UR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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 ), 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)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), and Jonchère, Laurent
Subjects: 0301 basic medicine, Programmed cell death, Iron, [SDV]Life Sciences [q-bio], Lipid peroxidation, Oxidative phosphorylation, Mitochondrion, medicine.disease_cause, Biochemistry, LMW iron, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Physiology (medical), Extracellular, medicine, Animals, Ferritin, NADPH oxidase, biology, Chemistry, Extracellular vesicles, Polycyclic aromatic hydrocarbons, Rats, Mitochondria, Cell biology, [SDV] Life Sciences [q-bio], Oxidative Stress, 030104 developmental biology, Hepatocytes, biology.protein, Lysosomes, 030217 neurology & neurosurgery, Oxidative stress
Abstract: International audience; A growing body of evidences indicate the major role of extracellular vesicles (EVs) as players of cell communication in the pathogenesis of liver diseases. EVs are membrane-enclosed vesicles released by cells into the extracellular environment. Oxidative stress is also a key component of liver disease pathogenesis, but no role for hepatocyte-derived EVs has yet been described in the development of this process. Recently, some polycyclic aromatic hydrocarbons (PAHs), widespread environmental contaminants, were demonstrated to induce EV release from hepatocytes. They are also well-known to trigger oxidative stress leading to cell death. Therefore, the aim of this work was to investigate the involvement of EVs derived from PAHs-treated hepatocytes (PAH-EVs) in possible oxidative damages of healthy recipient hepatocytes, using both WIF-B9 and primary rat hepatocytes. We first showed that the release of EVs from PAHs -treated hepatocytes depended on oxidative stress. PAH-EVs were enriched in proteins related to oxidative stress such as NADPH oxidase and ferritin. They were also demonstrated to contain more iron. PAH-EVs could then induce oxidative stress in recipient hepatocytes, thereby leading to apoptosis. Mitochondria and lysosomes of recipient hepatocytes exhibited significant structural alterations. All those damages were dependent on internalization of EVs that reached lysosomes with their cargoes. Lysosomes thus appeared as critical organelles for EVs to induce apoptosis. In addition, pro-oxidant components of PAH-EVs, e.g. NADPH oxidase and iron, were revealed to be necessary for this cell death.
Published: 2020

17. Obesity III: Obesogen assays: Limitations, strengths, and new directions

Author: Christopher D. Kassotis, Frederick S. vom Saal, Patrick J. Babin, Dominique Lagadic-Gossmann, Helene Le Mentec, Bruce Blumberg, Nicole Mohajer, Antoine Legrand, Vesna Munic Kos, Corinne Martin-Chouly, Normand Podechard, Sophie Langouët, Charbel Touma, Robert Barouki, Min Ji Kim, Karine Audouze, Mahua Choudhury, Nitya Shree, Amita Bansal, Sarah Howard, Jerrold J. Heindel, Chard-Hutchinson, Xavier, Wayne State University [Detroit], University of Missouri [Columbia] (Mizzou), University of Missouri System, Université de Bordeaux (UB), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), University of California [Irvine] (UC Irvine), University of California (UC), Karolinska Institute, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 Paris Cité (UPCité), Texas A&M University [College Station], Australian National University (ANU), and Healthy Environment and Endocrine Disruptor Strategies (HEEDS)
Subjects: Pharmacology, Adipogenesis, Obesity, Zebrafish, [SDV]Life Sciences [q-bio], Mesenchymal stem cells, Cell Differentiation, Pharmacology and Pharmaceutical Sciences, Biochemistry, Article, [SDV] Life Sciences [q-bio], Mice, 3T3-L1 Cells, Adipocytes, 3T3-L1, Animals, Generic health relevance, Biochemistry and Cell Biology, Pharmacology & Pharmacy, Caenorhabditis elegans
Abstract: International audience; There is increasing evidence of a role for environmental contaminants in disrupting metabolic health in both humans and animals. Despite a growing need for well-understood models for evaluating adipogenic and potential obesogenic contaminants, there has been a reliance on decades-old in vitro models that have not been appropriately managed by cell line providers. There has been a quick rise in available in vitro models in the last ten years, including commercial availability of human mesenchymal stem cell and preadipocyte models; these models require more comprehensive validation but demonstrate real promise in improved translation to human metabolic health. There is also progress in developing three-dimensional and co-culture techniques that allow for the interrogation of a more physiologically relevant state. While diverse rodent models exist for evaluating putative obesogenic and/or adipogenic chemicals in a physiologically relevant context, increasing capabilities have been identified for alternative model organisms such as Drosophila, C. elegans, zebrafish, and medaka in metabolic health testing. These models have several appreciable advantages, including most notably their size, rapid development, large brood sizes, and ease of high-resolution lipid accumulation imaging throughout the organisms. They are anticipated to expand the capabilities of metabolic health research, particularly when coupled with emerging obesogen evaluation techniques as described herein.
Published: 2022

18. Obesity II: Establishing causal links between chemical exposures and obesity

Author: Jerrold J. Heindel, Sarah Howard, Keren Agay-Shay, Juan P. Arrebola, Karine Audouze, Patrick J. Babin, Robert Barouki, Amita Bansal, Etienne Blanc, Matthew C. Cave, Saurabh Chatterjee, Nicolas Chevalier, Mahua Choudhury, David Collier, Lisa Connolly, Xavier Coumoul, Gabriella Garruti, Michael Gilbertson, Lori A. Hoepner, Alison C. Holloway, George Howell, Christopher D. Kassotis, Mathew K. Kay, Min Ji Kim, Dominique Lagadic-Gossmann, Sophie Langouet, Antoine Legrand, Zhuorui Li, Helene Le Mentec, Lars Lind, P. Monica Lind, Robert H. Lustig, Corinne Martin-Chouly, Vesna Munic Kos, Normand Podechard, Troy A. Roepke, Robert M. Sargis, Anne Starling, Craig R. Tomlinson, Charbel Touma, Jan Vondracek, Frederick vom Saal, Bruce Blumberg, Jonchère, Laurent, Healthy Environment and Endocrine Disruptor Strategies (HEEDS), Universidad de Granada = University of Granada (UGR), 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 Paris Cité (UPCité), Université de Bordeaux (UB), Australian National University - Department of engineering (ANU), Australian National University (ANU), University of Louisville, University of South Carolina [Columbia], Université Côte d'Azur (UCA), Texas A&M University System, East Carolina University [Greenville] (ECU), University of North Carolina System (UNC), Queen's University [Belfast] (QUB), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), University of Stirling, State University of New York (SUNY), McMaster University [Hamilton, Ontario], Mississippi State University [Mississippi], Wayne State University [Detroit], École des Hautes Études en Santé Publique [EHESP] (EHESP), 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 ), University of California [Irvine] (UC Irvine), University of California (UC), Uppsala Universitet [Uppsala], University of California [San Francisco] (UC San Francisco), Karolinska Institute, EHESP-Irset (EHESP-Irset), Rutgers University System (Rutgers), University of Illinois [Chicago] (UIC), University of Illinois System, University of North Carolina [Chapel Hill] (UNC), Geisel School of Medicine at Dartmouth, Institute of Biophysics of the Czech Academy of Sciences (IBP / CAS), Czech Academy of Sciences [Prague] (CAS), University of Missouri [Columbia] (Mizzou), and University of Missouri System
Subjects: Adipocyte differentiation, [SDV]Life Sciences [q-bio], Endocrine Disruptors, Obesogen, Biochemistry, Article, Oral and gastrointestinal, Genetics, Humans, Pharmacology & Pharmacy, Obesity, Child, Preschool, Endocrine disruptor, Weight gain, Metabolic and endocrine, Nutrition, Pharmacology, Adipogenesis, Prevention, Pharmacology and Pharmaceutical Sciences, Environmental Exposure, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Adipose Tissue, Child, Preschool, Biochemistry and Cell Biology, Digestive Diseases
Abstract: International audience; Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.
Published: 2021

19. Combustion Particle-Induced Changes in Calcium Homeostasis: A Contributing Factor to Vascular Disease?

Author: Dominique Lagadic-Gossmann, Johan Øvrevik, Jørn A. Holme, Eric Le Ferrec, Bendik Christian Brinchmann, Norwegian Institute of Public Health [Oslo] (NIPH), 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 ), University of Oslo (UiO), 228143, Norges Forskningsråd, 260381, Norges Forskningsråd, ReseachCouncil of Norway, 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: Traffic-Related Pollution, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Toxicology, Risk Assessment, Calcium in biology, Receptors, G-Protein-Coupled, 03 medical and health sciences, Transient receptor potential channel, Transient Receptor Potential Channels, 0302 clinical medicine, 11. Sustainability, Basic Helix-Loop-Helix Transcription Factors, Animals, Homeostasis, Humans, Vascular Diseases, Endothelial dysfunction, Receptor, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Aryl hydrocarbon receptor, Vehicle Emissions, G protein-coupled receptor, Calcium signaling, Calcium metabolism, Voltage-dependent calcium channel, biology, Chemistry, Environmental Exposure, Prognosis, Diesel exhaust particles, Polycyclic aromatic hydrocarbons, 3. Good health, Cell biology, carbohydrates (lipids), Receptors, Aryl Hydrocarbon, 13. Climate action, 030220 oncology & carcinogenesis, biology.protein, Calcium, Particulate Matter, lipids (amino acids, peptides, and proteins), Endothelium, Vascular, Cardiology and Cardiovascular Medicine
Abstract: Air pollution is the leading environmental risk factor for disease and premature death in the world. This is mainly due to exposure to urban air particle matter (PM), in particular, fine and ultrafine combustion-derived particles (CDP) from traffic-related air pollution. PM and CDP, including particles from diesel exhaust (DEP), and cigarette smoke have been linked to various cardiovascular diseases (CVDs) including atherosclerosis, but the underlying cellular mechanisms remain unclear. Moreover, CDP typically consist of carbon cores with a complex mixture of organic chemicals such as polycyclic aromatic hydrocarbons (PAHs) adhered. The relative contribution of the carbon core and adhered soluble components to cardiovascular effects of CDP is still a matter of discussion. In the present review, we summarize evidence showing that CDP affects intracellular calcium regulation, and argue that CDP-induced impairment of normal calcium control may be a critical cellular event through which CDP exposure contributes to development or exacerbation of cardiovascular disease. Furthermore, we highlight in vitro research suggesting that adhered organic chemicals such as PAHs may be key drivers of these responses. CDP, extractable organic material from CDP (CDP-EOM), and PAHs may increase intracellular calcium levels by interacting with calcium channels like transient receptor potential (TRP) channels, and receptors such as G protein-coupled receptors (GPCR; e.g., beta-adrenergic receptors [βAR] and protease-activated receptor 2 [PAR-2]) and the aryl hydrocarbon receptor (AhR). Clarifying a possible role of calcium signaling and mechanisms involved may increase our understanding of how air pollution contributes to CVD.
Published: 2019

20. Effet des acides gras polyinsaturés à longue chaîne n-3 sur le remodelage membranaire induit par les toxiques chimiques : retentissement sur la mort cellulaire

Author: Normand Podechard, Odile Sergent, Dominique Lagadic-Gossmann, Chard-Hutchinson, Xavier, 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 ), and École des Hautes Études en Santé Publique [EHESP] (EHESP)
Subjects: 0303 health sciences, Nutrition and Dietetics, Ethanol, 030309 nutrition & dietetics, Medicine (miscellaneous), EPA, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, DHA, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, 03 medical and health sciences, Liver, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Benzo(a)pyrene, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Homeostasis of plasma membrane is crucial for the regulation of many cell processes such as inflammation, cell proliferation, migration or death. This especially dynamic cell structure can undergo alteration when exposed to a wide range of chemical toxicants, thus triggering a membrane stress signal that can change the activation of intracellular signalling pathways, involved in such phenomena. Yet, long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) are described as capable of changing physicochemical properties of membranes. Thus, LC n-3 PUFA can possibly counteract or potentiate the effects of chemical toxicants with a membrane action. In this paper, we will mainly be interested in hepatotoxicants, notably benzo(a)pyrene, an environmental pollutant of the polycyclic aromatic hydrocarbon family, also found in cigarette smoke, and ethanol, the hepatoxicant prototype, whose human exposure is linked to lifestyle., L’homéostasie de la membrane plasmique est essentielle à la régulation de plusieurs processus cellulaires comme l’inflammation, la prolifération, la migration ou la mort cellulaire. Cette structure très dynamique peut subir des altérations lors de son exposition à de nombreux toxiques chimiques, déclenchant un signal de stress membranaire, qui peut modifier l’activation de voies de signalisation intracellulaire impliquées dans ces différents phénomènes. Or, les acides gras polyinsaturés à longue chaîne n-3 (AGPI LC n-3) sont décrits comme capables de modifier les propriétés physicochimiques des membranes. Les AGPI LC n-3 sont donc susceptibles de limiter ou de potentialiser les effets des toxiques chimiques à action membranaire. Dans cet article, nous nous intéresserons principalement aux hépatotoxiques, notamment le benzo(a)pyrène, un contaminant de l’environnement de la famille des hydrocarbures aromatiques polycycliques, trouvé également dans la fumée de cigarette, et l’éthanol, le prototype des toxiques du foie, dont l’exposition humaine est liée au mode de vie.
Published: 2019

21. Organic chemicals from diesel exhaust particles affects intracellular calcium, inflammation and β-adrenoceptors in endothelial cells

Author: Dominique Lagadic-Gossmann, Johan Øvrevik, Eric Le Ferrec, Bendik Christian Brinchmann, Normand Podechard, Jørn A. Holme, University of Oslo (UiO), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Norwegian Institute of Public Health [Oslo] (NIPH), The work was supported by the Research Council of Norway through the Environmental Exposures and Health Outcomes-program (grant no. 228143)., 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: 0301 basic medicine, genetic structures, Carazolol, Inflammation, calcium signaling, Toxicology, complex mixtures, endothelial dysfunction, Calcium in biology, Cell Line, Receptors, G-Protein-Coupled, 03 medical and health sciences, diesel exhaust particles, 0302 clinical medicine, Receptors, Adrenergic, beta, medicine, Humans, Receptor, PAR-2, beta adrenoceptors, Protease-activated receptor, Interleukin 8, Organic Chemicals, Endothelial dysfunction, ComputingMilieux_MISCELLANEOUS, Vehicle Emissions, Calcium signaling, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Chemistry, Endothelial Cells, General Medicine, medicine.disease, eye diseases, Endothelial stem cell, 030104 developmental biology, Gene Expression Regulation, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Biophysics, Calcium, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, Inflammation Mediators, medicine.symptom, protease activated receptor, 030217 neurology & neurosurgery, extractable organic material
Abstract: Exposure to diesel exhaust particles (DEP) may contribute to endothelial dysfunction and cardiovascular disease. DEP, extractable organic material from DEP (DEP-EOM) and certain PAHs seem to trigger [Ca2+]i increase as well as inflammation via GPCRs like βARs and PAR-2. In the present study we explored the involvement of βARs and PAR-2 in effects of DEP-EOM on [Ca2+]i and expression of inflammation-associated genes in the endothelial cell-line HMEC-1. We exposed the human microvascular endothelial cell line HMEC-1 to DEP-EOM fractionated by sequential extraction with solvents of increasing polarity: n-hexane (n-Hex-EOM), dichloromethane (DCM-EOM), methanol (Methanol-EOM) and water (Water-EOM). While Methanol-EOM and Water-EOM had no marked effects, n-Hex-EOM and DCM-EOM enhanced [Ca2+]i (2–3 times baseline) and expression of inflammation-associated genes (IL-1α, IL-1β, COX-2 and CXCL8; 2–15 times baseline) in HMEC-1. The expression of βARs (60–80% of baseline) and βAR-inhibitor carazolol suppressed the increase in [Ca2+]i induced by both n-Hex- and DCM-EOM. Carazolol as well as the Ca2+-channel inhibitor SKF-96365 reduced the DCM-EOM-induced pro-inflammatory gene-expression. Overexpression of βARs increased DCM-EOM-induced [Ca2+]i responses in HEK293 cells, while βAR-overexpression suppressed [Ca2+]i responses from n-Hex-EOM. Furthermore, the PAR-2-inhibitor ENMD-1068 attenuated [Ca2+]i responses to DCM-EOM, but not n-Hex-EOM in HMEC-1. The results suggest that βAR and PAR-2 are partially involved in effects of complex mixtures of chemicals extracted from DEP on calcium signalling and inflammation-associated genes in the HMEC-1 endothelial cell-line.
Published: 2019

22. Corrigendum to 'Obesity II: Establishing causal links between chemical exposures and obesity' [Biochem. Pharmacol. 199 (2022) 115015]

Author: Jerrold J. Heindel, Sarah Howard, Keren Agay-Shay, Juan P. Arrebola, Karine Audouze, Patrick J. Babin, Robert Barouki, Amita Bansal, Etienne Blanc, Matthew C. Cave, Saurabh Chatterjee, Nicolas Chevalier, Mahua Choudhury, David Collier, Lisa Connolly, Xavier Coumoul, Gabriella Garruti, Michael Gilbertson, Lori A. Hoepner, Alison C. Holloway, George Howell, Christopher D. Kassotis, Mathew K. Kay, Min Ji Kim, Dominique Lagadic-Gossmann, Sophie Langouet, Antoine Legrand, Zhuorui Li, Helene Le Mentec, Lars Lind, P. Monica Lind, Robert H. Lustig, Corinne Martin-Chouly, Vesna Munic Kos, Normand Podechard, Troy A. Roepke, Robert M. Sargis, Anne Starling, Craig R. Tomlinson, Charbel Touma, Jan Vondracek, Frederick vom Saal, and Bruce Blumberg
Subjects: Pharmacology, Biochemistry
Published: 2022

23. MEHP/ethanol co-exposure favors the death of steatotic hepatocytes, possibly through CYP4A and ADH involvement

Author: Maelle Bescher, Dominique Lagadic-Gossmann, Corinne Martin-Chouly, Odile Sergent, Muhammad Imran, Normand Podechard, Louis Legoff, Isabelle Gallais, Arnaud Tête, Lydie Sparfel, 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 ), This work was supported by Agence Nationale de la Recherche (ANR) [STEATOX project: 'ANR-13-CESA-0009'], as well as by Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (Anses) (Z-MENACE project: N° 2019/1/128)., ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique(2013), 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: medicine.medical_specialty, Programmed cell death, DNA damage, Toxicology, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, 0404 agricultural biotechnology, Internal medicine, Diethylhexyl Phthalate, NAFLD, medicine, Animals, Humans, oxidative stress, Ethanol metabolism, Zebrafish larvae, 030304 developmental biology, Alcohol dehydrogenase, 0303 health sciences, biology, Cell Death, Ethanol, DEHP, AhR, Phthalate, Alcohol Dehydrogenase, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 04 agricultural and veterinary sciences, General Medicine, medicine.disease, 040401 food science, 3. Good health, Fatty Liver, Endocrinology, chemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Toxicity, biology.protein, Hepatocytes, Steatosis, Cytochrome P-450 CYP4A, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Oxidative stress, Food Science
Abstract: International audience; Liver steatosis has been associated with various etiological factors (obesity, alcohol, environmental contaminants). How those factors work together to induce steatosis progression is still scarcely evaluated. Here, we tested whether phthalates could potentiate death of steatotic hepatocytes when combined with ethanol. Pre-steatotic WIF-B9 hepatocytes were co-exposed to mono(2-ethylhexyl) (MEHP, 500 nM; main metabolite of di(2-ethylhexyl) phthalate or DEHP) and ethanol (5 mM) for 5 days. An increased apoptotic death was detected, involving a DNA damage response. Using 4-Methypyrazole to inhibit ethanol metabolism, and CH-223191 to antagonize the AhR receptor, we found that an AhR-dependent increase in alcohol dehydrogenase (ADH) activity was essential for cell death upon MEHP/ethanol co-exposure. Toxicity was also prevented by HET0016 to inhibit the cytochrome P450 4A (CYP4A). Using the antioxidant thiourea, a role for oxidative stress was uncovered, notably triggering DNA damage. Finally, co-exposing the in vivo steatosis model of high fat-diet (HFD)-zebrafish larvae to DEHP (2.56 nM)/ethanol (43 mM), induced the pathological progression of liver steatosis alongside an increased Cyp4t8 (human CYP4A homolog) mRNA expression. Altogether, these results further emphasized the deleterious impact of co-exposures to ethanol/ environmental pollutant towards steatosis pathological progression, and unraveled a key role for ADH and CYP4A in such effects.
Published: 2020

24. Obesity I: Overview and molecular and biochemical mechanisms

Author: Robert H. Lustig, David Collier, Christopher Kassotis, Troy A. Roepke, Min Ji Kim, Etienne Blanc, Robert Barouki, Amita Bansal, Matthew C. Cave, Saurabh Chatterjee, Mahua Choudhury, Michael Gilbertson, Dominique Lagadic-Gossmann, Sarah Howard, Lars Lind, Craig R. Tomlinson, Jan Vondracek, Jerrold J. Heindel, University of California [San Francisco] (UC San Francisco), University of California (UC), East Carolina University [Greenville] (ECU), University of North Carolina System (UNC), Wayne State University [Detroit], Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers), 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 Paris Cité (UPCité), Australian National University (ANU), University of Louisville, University of South Carolina [Columbia], Texas A&M University [College Station], University of Stirling, 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 ), Healthy Environment and Endocrine Disruptor Strategies (HEEDS), Uppsala University, Geisel School of Medicine at Dartmouth, Institute of Biophysics of the Czech Academy of Sciences (IBP / CAS), Czech Academy of Sciences [Prague] (CAS), Lagadic-Gossmann, Dominique, University of California [San Francisco] (UCSF), University of California, 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 École des Hautes Études en Santé Publique [EHESP] (EHESP)
Subjects: Leptin, Pharmacology, Energy balance, Microbiome, Obesity, [SDV]Life Sciences [q-bio], Adipose tissue, Metabolism, Hormone receptors, Biochemistry, Article, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Adipocytes, Humans, Insulin, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Energy Metabolism
Abstract: International audience; Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight people is now greater than those underweight. Obesity is a multifactorial condition, and as such, many components contribute to its development and pathogenesis. This is the first of three companion reviews that consider obesity. This review focuses on the genetics, viruses, insulin resistance, inflammation, gut microbiome, and circadian rhythms that promote obesity, along with hormones, growth factors, and organs and tissues that control its development. It shows that the regulation of energy balance (intake vs. expenditure) relies on the interplay of a variety of hormones from adipose tissue, gastrointestinal tract, pancreas, liver, and brain. It details how integrating central neurotransmitters and peripheral metabolic signals (e.g., leptin, insulin, ghrelin, peptide YY(3-36)) is essential for controlling energy homeostasis and feeding behavior. It describes the distinct types of adipocytes and how fat cell development is controlled by hormones and growth factors acting via a variety of receptors, including peroxisome proliferator-activated receptor-gamma, retinoid X, insulin, estrogen, androgen, glucocorticoid, thyroid hormone, liver X, constitutive androstane, pregnane X, farnesoid, and aryl hydrocarbon receptors. Finally, it demonstrates that obesity likely has origins in utero. Understanding these biochemical drivers of adiposity and metabolic dysfunction throughout the life cycle lends plausibility and credence to the "obesogen hypothesis" (i.e., the importance of environmental chemicals that disrupt these receptors to promote adiposity or alter metabolism), elucidated more fully in the two companion reviews.
Published: 2022

25. Moderate chronic ethanol consumption exerts beneficial effects on nonalcoholic fatty liver in mice fed a high-fat diet possible role of higher formation of triglycerides enriched in monounsaturated fatty acids

Author: Dominique Lagadic-Gossmann, Karima Begriche, Simon Bucher, Viviane Trak-Smayra, François Tiaho, Cédric Coulouarn, Bernard Fromenty, Daniel Catheline, Vincent Rioux, Grégory Pinon, Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), 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), Université Saint-Joseph de Beyrouth (USJ), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), ANR-13-CESA-0009, Agence Nationale de la Recherche, ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique(2013), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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: Male, medicine.medical_specialty, Mouse, Medicine (miscellaneous), Diet, High-Fat, Fatty Acids, Monounsaturated, Collagen fibril organization, Palmitic acid, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Internal medicine, NAFLD, Nonalcoholic fatty liver disease, medicine, Animals, Glycolysis, Transcriptomics, Triglycerides, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Nutrition and Dietetics, Ethanol, Chemistry, Fatty liver, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Lipids, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Liver, Mitochondrial respiratory chain complex assembly, 030211 gastroenterology & hepatology, Steatosis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Leukocyte chemotaxis
Abstract: International audience; Purpose - Several clinical studies suggested that light-to-moderate alcohol intake could alleviate nonalcoholic fatty liver disease (NAFLD), but the underlying mechanism is still poorly understood. Methods - Mice fed a high-fat diet (HFD) were submitted or not to moderate ethanol intake for 3 months (ca. 10 g/kg/day) via drinking water. Biochemical, analytical and transcriptomic analyses were performed in serum and liver. Results - Serum ethanol concentrations in ethanol-treated HFD mice comprised between 0.5 and 0.7 g/l throughout the experiment. NAFLD improvement was observed in ethanol-treated HFD mice as assessed by reduced serum transaminase activity. This was associated with less microvesicular and more macrovacuolar steatosis, the absence of apoptotic hepatocytes and a trend towards less fibrosis. Liver lipid analysis showed increased amounts of fatty acids incorporated in triglycerides and phospholipids, reduced proportion of palmitic acid in total lipids and higher desaturation index, thus suggesting enhanced stearoyl-coenzyme A desaturase activity. mRNA expression of several glycolytic and lipogenic enzymes was upregulated. Genome-wide expression profiling and gene set enrichment analysis revealed an overall downregulation of the expression of genes involved in collagen fibril organization and leukocyte chemotaxis and an overall upregulation of the expression of genes involved in oxidative phosphorylation and mitochondrial respiratory chain complex assembly. In addition, mRNA expression of several proteasome subunits was upregulated in ethanol-treated HFD mice. Conclusions - Moderate chronic ethanol consumption may alleviate NAFLD by several mechanisms including the generation of non-toxic lipid species, reduced expression of profibrotic and proinflammatory genes, restoration of mitochondrial function and possible stimulation of proteasome activity.
Published: 2020

26. Microalgal carotenoids and phytosterols regulate biochemical mechanisms involved in human health and disease prevention

Author: Manon Le Goff, Dominique Lagadic-Gossmann, Virginie Mimouni, Claire Mayer, Lionel Ulmann, Eric Le Ferrec, Benoît Schoefs, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Mer, molécules et santé EA 2160 (MMS), Le Mans Université (UM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), IUT de Laval, Le Mans Université (UM), Collectivités Locales Mayennaises and the French Ministère de l’Enseignement Supérieur de la Recherche et de l’Innovation, Université de Rennes (UR), Le Mans Université (UM)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: 0301 basic medicine, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Xanthophylls, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Metabolic Diseases, Astaxanthin, Neoplasms, Microalgae, Humans, Cell signaling pathway regulation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Carotenoid, Fatty acid synthesis, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, 030102 biochemistry & molecular biology, Kinase, Cholesterol, Phytosterols, General Medicine, Peroxisome, Lipid Metabolism, Sitosterols, Sterol, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 030104 developmental biology, chemistry, Cardiovascular Diseases, Dietary Supplements, Carbohydrate Metabolism, Signal transduction, Chronic disease prevention, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Signal Transduction
Abstract: International audience; Microalgae are photosynthetic microorganisms that produce numerous bioactive molecules that can be used as food supplement to prevent chronic disease installation. Indeed, they produce phycobiliproteins, polysaccharides, lipids, carotenoids and sterolic compounds. The use of microalgae in human nutrition provide a mixture of these molecules with synergistic effect. The aim of this review is to present the specific roles played by the xanthophylls, and specifically astaxanthin and fucoxanthin, two high added value carotenoids, and by microalgal phytosterols such as β-sitosterol, campesterol and stigmasterol on several cell mechanisms involved in the prevention of cardiometabolic diseases and cancers. This review explains how these microalgal molecules modulate cell signaling pathways involved in carbohydrate and lipid metabolisms, inflammation, apoptosis, invasion and metastasis. Xanthophylls and phytosterols are involved in the reduction of inflammatory markers in relation with the regulation of the c-Jun N-terminal kinases and nuclear factor-kappa B signaling pathways, and suppression of production of pro-inflammatory mediators. Xanthophylls act on glucose and lipid metabolisms via both the upregulation of peroxisome proliferator-activated receptors (PPARs) and glucose transporters and its effects on the expression of enzymes involved in fatty acid synthesis and cholesterol metabolism. Their anti-cancer effects are related to the induction of intrinsic apoptosis due to down-regulation of key regulatory kinases. The anti-angiogenesis, anti-proliferative and anti-invasive effects are correlated with decreased production of endothelial growth factors and of matrix metalloproteinases. Phytosterols have a major role on cholesterol absorption via modification of the activities of Niemann-Pick C1 like 1 and ATP-binding cassette transporters and on cholesterol esterification. Their action are also related with the modulation of PPARs and sterol regulatory element-binding protein-1 activities.
Published: 2019

27. PAHs increase the production of extracellular vesicles both in vitro in endothelial cells and in vivo in urines from rats

Author: Dominique Lagadic-Gossmann, Agnès Burel, Manon Le Goff, Nathalie Grova, Normand Podechard, Remi Latour, Soizic Chevance, Fabienne Gauffre, Eric Le Ferrec, Brice M.R. Appenzeller, Odile Sergent, Lionel Ulmann, 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 ), Luxembourg Institute of Health (LIH), Composés Alimentaires : Biofonctionnalités et risques Neurotoxiques (CALBINOTOX), Université de Lorraine (UL), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), IUT de Laval, Le Mans Université (UM), Mer, molécules et santé EA 2160 (MMS), Le Mans Université (UM)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Programme Environnement-Santé-Travail, ITMO, CCSD, Accord Elsevier, 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 ), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, and Université de Nantes (UN)-Université de Nantes (UN)-Le Mans Université (UM)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST)
Subjects: 010504 meteorology & atmospheric sciences, Health, Toxicology and Mutagenesis, Endothelial cells, Cell, 010501 environmental sciences, Urine, Toxicology, Exosomes, Small EVs, 01 natural sciences, [CHIM] Chemical Sciences, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, Aryl hydrocarbon receptor, biology, Chemistry, Vesicle, General Medicine, Extracellular vesicles, Pollution, Polycyclic aromatic hydrocarbons, Body Fluids, 3. Good health, Cell biology, Endothelial stem cell, medicine.anatomical_structure, Environmental Pollutants, Female, Microvesicles, Environmental Monitoring, [SDV.CAN]Life Sciences [q-bio]/Cancer, Large EVs, Cell Line, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, medicine, Extracellular, Animals, Humans, [CHIM]Chemical Sciences, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 0105 earth and related environmental sciences, Environmental Exposure, In vitro, Rats, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Receptors, Aryl Hydrocarbon, 13. Climate action, biology.protein, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Biomarkers
Abstract: Environmental contaminants, to which humans are widely exposed, cause or worsen several diseases, like cardiovascular diseases and cancers. Among these molecules, polycyclic aromatic hydrocarbons (PAHs) stand out since they are ubiquitous pollutants found in ambient air and diet. Because of their toxic effects, public Health agencies promote development of research studies aiming at increasing the knowledge about PAHs and the discovery of biomarkers of exposure and/or effects. Extracellular vesicles (EVs), including small extracellular vesicles (S-EVs or exosomes) and large extracellular vesicles (L-EVs or microvesicles), are delivery systems for multimolecular messages related to the nature and status of the originating cells. Because they are produced by all cells and detected within body fluids, EV releases could act as cell responses and thereby serve as biomarkers. To test whether EVs can serve as biomarkers of PAHs exposure, we evaluate the effects of these pollutants on EV production using an in vitro approach (human endothelial cell line, HMEC-1) and an in vivo approach (urine samples from PAHs-exposed rats). Our study indicates that, i) PAH exposure increases in vitro the EV production by endothelial cells and in vivo the release of EVs in urine, and that the stimulating effects of PAHs concern both S-EVs and L-EVs; ii) PAH exposure and more particularly exposure to B[a]P, can influence the composition of exosomes produced by endothelial cells; iii) the aryl hydrocarbon receptor, a cytosolic receptor associated to most deleterious effects of PAHs, would be involved in the PAH effects on the release of S-EVs, but not L-EVs. These results suggest that EVs may have utility for monitoring exposure to PAHs, and more particularly to B[a]P, considered as reference PAH, and to detect the related early cellular response prior to end-organ damages.
Published: 2019

28. Lipophilic components of diesel exhaust particles induce pro-inflammatory responses in human endothelial cells through AhR dependent pathway(s)

Author: Johan Øvrevik, Magne Refsnes, Dominique Lagadic-Gossmann, Jørn A. Holme, Eric Le Ferrec, Bendik Christian Brinchmann, Klara Kukowski, Alena Kubátová, Krisztina Szöke, Arno C. Gutleb, Jan E. Brinchmann, Tonje Skuland, Mia H. Rambøl, Marit Låg, Elisa Moschini, Per E. Schwarze, Jonchère, Laurent, Department of Air Pollution and Noise, Domain of Infection Control, Environment and Health [Oslo, Norway], Norwegian Institute of Public Health [Oslo] (NIPH), Division of Laboratory Medicine [Oslo, Norway] (Faculty of Medicine), University of Oslo (UiO), Department of Immunology (Norwegian Center for Stem Cell Research), Oslo University Hospital [Oslo], Luxembourg Institute of Science and Technology (LIST), University of North Dakota [Grand Forks] (UND), 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 de Rennes 1 - Faculté des sciences pharmaceutiques et biologiques (UR1 Pharmacie), Université de Rennes (UR), The contribution of EM and ACG was performed in the framework of the internally funded 'In vitro models for the prediction of respiratory irritation and sensitization - IMPERIS' project (LIST). BC Brinchmann was supported by a travel exchange grant from Rennes Métropole, to realize part of his PhD in Rennes, France. The work at NIPH, including two travel grants were supported by the Research Council of Norway, through the Environmental Exposures and Health Outcomes-program (grant no. 228143)., Université de Rennes - Faculté des sciences pharmaceutiques et biologiques (UR Pharmacie), 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 ), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: 0301 basic medicine, Diesel exhaust, Health, Toxicology and Mutagenesis, Endothelial cells, Gene Expression, Chromosomal translocation, 010501 environmental sciences, Toxicology, 01 natural sciences, Gene expression, Endothelial dysfunction, Polycyclic Aromatic Hydrocarbons, ComputingMilieux_MISCELLANEOUS, Aryl hydrocarbon receptor, Vehicle Emissions, biology, Chemistry, General Medicine, respiratory system, Cardiovascular disease, 3. Good health, Cell biology, medicine.anatomical_structure, Cytokines, medicine.symptom, Matrix Metalloproteinase 1, Signal Transduction, Endothelium, Air pollution, lcsh:Industrial hygiene. Industrial welfare, Inflammation, 03 medical and health sciences, lcsh:RA1190-1270, Organic compounds, medicine, Humans, Secretion, 0105 earth and related environmental sciences, lcsh:Toxicology. Poisons, Research, medicine.disease, Diesel exhaust particles, Atherosclerosis, 3D tri-culture, 030104 developmental biology, Receptors, Aryl Hydrocarbon, Cyclooxygenase 2, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Microvessels, biology.protein, Nanoparticles, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, lcsh:HD7260-7780.8
Abstract: Background Exposure to traffic-derived particulate matter (PM), such as diesel exhaust particles (DEP), is a leading environmental cause of cardiovascular disease (CVD), and may contribute to endothelial dysfunction and development of atherosclerosis. It is still debated how DEP and other inhaled PM can contribute to CVD. However, organic chemicals (OC) adhered to the particle surface, are considered central to many of the biological effects. In the present study, we have explored the ability of OC from DEP to reach the endothelium and trigger pro-inflammatory reactions, a central step on the path to atherosclerosis. Results Exposure-relevant concentrations of DEP (0.12 μg/cm2) applied on the epithelial side of an alveolar 3D tri-culture, rapidly induced pro-inflammatory and aryl hydrocarbon receptor (AhR)-regulated genes in the basolateral endothelial cells. These effects seem to be due to soluble lipophilic constituents rather than particle translocation. Extractable organic material of DEP (DEP-EOM) was next fractionated with increasing polarity, chemically characterized, and examined for direct effects on pro-inflammatory and AhR-regulated genes in human microvascular endothelial (HMEC-1) cells and primary human endothelial cells (PHEC) from four healthy donors. Exposure-relevant concentrations of lipophilic DEP-EOM (0.15 μg/cm2) induced low to moderate increases in IL-1α, IL-1β, COX2 and MMP-1 gene expression, and the MMP-1 secretion was increased. By contrast, the more polar EOM had negligible effects, even at higher concentrations. Use of pharmacological inhibitors indicated that AhR and protease-activated receptor-2 (PAR-2) were central in regulation of EOM-induced gene expression. Some effects also seemed to be attributed to redox-responses, at least at the highest exposure concentrations tested. Although the most lipophilic EOM, that contained the majority of PAHs and aliphatics, had the clearest low-concentration effects, there was no straight-forward link between chemical composition and biological effects. Conclusion Lipophilic and semi-lipophilic chemicals seemed to detach from DEP, translocate through alveolar epithelial cells and trigger pro-inflammatory reactions in endothelial cells at exposure-relevant concentrations. These effects appeared to be triggered by AhR agonists, and involve PAR-2 signaling. Electronic supplementary material The online version of this article (10.1186/s12989-018-0257-1) contains supplementary material, which is available to authorized users.
Published: 2018

29. Influence of Microalgae Extracts on the Toxicity of a Carcinogenic Polycyclic Aromatic Hydrocarbon, Benzo(a)pyrene, in Endothelial Cells

Author: Dominique Lagadic-Gossmann, Odile Sergent, Lionel Ulmann, Manon Le Goff, Eric Le Ferrec, Antoine Delbrut, and Rémi Pradelles
Subjects: Carcinogenic Polycyclic Aromatic Hydrocarbon, chemistry.chemical_compound, Benzo(a)pyrene, Chemistry, Environmental chemistry, Toxicity
Published: 2019

30. Disturbances in H

Author: Dominique, Lagadic-Gossmann, Kévin, Hardonnière, Baharia, Mograbi, Odile, Sergent, and Laurence, Huc
Subjects: Liver, Carcinogenesis, Neoplasms, Benzo(a)pyrene, Carcinogens, Animals, Humans, Environmental Exposure, Protons
Abstract: Despite the improvement of diagnostic methods and anticancer therapeutics, the human population is still facing an increasing incidence of several types of cancers. According to the World Health Organization, this growing trend would be partly linked to our environment, with around 20% of cancers stemming from exposure to environmental contaminants, notably chemicals like polycyclic aromatic hydrocarbons (PAHs). PAHs are widespread pollutants in our environment resulting from incomplete combustion or pyrolysis of organic material, and thus produced by both natural and anthropic sources; notably benzo[a]pyrene (B[a]P), i.e. the prototypical molecule of this family, that can be detected in cigarette smoke, diesel exhaust particles, occupational-related fumes, and grilled food. This molecule is a well-recognized carcinogen belonging to group 1 carcinogens. Indeed, it can target the different steps of the carcinogenic process and all cancer hallmarks. Interestingly, H
Published: 2019

31. Protective Action of Ostreococcus tauri and Phaeodactylum tricornutum Extracts towards Benzo[a]Pyrene-Induced Cytotoxicity in Endothelial Cells

Author: Agnès Burel, Lionel Ulmann, Dominique Lagadic-Gossmann, Manon Le Goff, Marie Quinton, Rémi Pradelles, Antoine Delbrut, Benoît Schoefs, Odile Sergent, Eric Le Ferrec, Maelle Bescher, Mer, molécules et santé EA 2160 (MMS), Le Mans Université (UM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Microphyt, Centre de Microscopie de Rennes (MRic), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), EST-2016/1/31, ITMO Cancer Plan 2014-2019, Concerto project, Cancéropôle Grand-Ouest / Région Bretagne, Laval Agglo, Collectivités Locales Mayennaises, Le Mans Université (UM)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, 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 de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: medicine.medical_treatment, [SDV]Life Sciences [q-bio], Pharmaceutical Science, Apoptosis, Phaeodactylum tricornutum, chemistry.chemical_compound, 0302 clinical medicine, Drug Discovery, Microalgae, Cytotoxicity, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, aryl hydrocarbon receptor, benzo[a]pyrene, endothelial cells, 3. Good health, Cytokine, Benzo(a)pyrene, Biochemistry, 030220 oncology & carcinogenesis, Toxicity, Pyrene, extracellular vesicles, cell protection, Cell Survival, Oceans and Seas, Context (language use), Article, Cell Line, 03 medical and health sciences, medicine, Cytochrome P-450 CYP1A1, Humans, cell viability, 030304 developmental biology, Biological Products, mRNA expression, Aryl hydrocarbon receptor, biology.organism_classification, cytokines, chemistry, 13. Climate action, Ostreococcus tauri, biology.protein
Abstract: Marine microalgae are known to be a source of bioactive molecules of interest to human health, such as n-3 polyunsaturated fatty acids (n-3 PUFAs) and carotenoids. The fact that some of these natural compounds are known to exhibit anti-inflammatory, antioxidant, anti-proliferative, and apoptosis-inducing effects, demonstrates their potential use in preventing cancers and cardiovascular diseases (CVDs). Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon (PAH), is an ubiquitous environmental pollutant known to contribute to the development or aggravation of human diseases, such as cancer, CVDs, and immune dysfunction. Most of these deleterious effects are related to the activation of the polycyclic aromatic hydrocarbon receptor (AhR). In this context, two ethanolic microalgal extracts with concentrations of 0.1 to 5 &micro, g/mL are tested, Ostreoccoccus tauri (OT) and Phaeodactylum tricornutum (PT), in order to evaluate and compare their potential effects towards B[a]P-induced toxicity in endothelial HMEC-1 cells. Our results indicate that the OT extract can influence the toxicity of B[a]P. Indeed, apoptosis and the production of extracellular vesicles were decreased, likely through the reduction of the expression of CYP1A1, a B[a]P bioactivation enzyme. Furthermore, the B[a]P-induced expression of the inflammatory cytokines IL-8 and IL1-&beta, was reduced. The PT extract only inhibited the expression of the B[a]P-induced cytokine IL-8 expression. The OT extract therefore seems to be a good candidate for counteracting the B[a]P toxicity.
Published: 2019

32. Disturbances in H dynamics during environmental carcinogenesis

Author: Dominique Lagadic-Gossmann, Baharia Mograbi, Odile Sergent, Kévin Hardonnière, Laurence Huc, Jonchère, Laurent, Contaminants et Environnements : Santé, Adaptabilité, Comportements et Usages - Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique - - STEATOX2013 - ANR-13-CESA-0009 - CESA - VALID, 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Contaminants & Stress Cellulaire (ToxAlim-COMICS), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, 17CE040-00, Institut National de la Santé et de la Recherche Médicale, French Ministry of Research, Région Bretagne, the Ligue contre le Cancer, the French National Agency for Research, ANR-13-CESA-0009, ANR, ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique(2013), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT), 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 ), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), and Lagadic-Gossmann, Dominique
Subjects: 0301 basic medicine, Diesel exhaust, Population, Médecine humaine et pathologie, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, [SDV.CAN] Life Sciences [q-bio]/Cancer, education, Carcinogen, Pollutant, education.field_of_study, 030102 biochemistry & molecular biology, benzo[a]pyrene, General Medicine, 3. Good health, Mitochondria, Intracellular pH, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Molecular Toxicology, 030104 developmental biology, Benzo(a)pyrene, chemistry, Extracellular acidosis, 13. Climate action, Environmental chemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Environmental Carcinogenesis, NHE1, Warburg effect, extracellular acidosis, mitochondria, intracellular pH, Pyrene, Human health and pathology
Abstract: International audience; Despite the improvement of diagnostic methods and anticancer therapeutics, the human population is still facing an increasing incidence of several types of cancers. According to the World Health Organization, this growing trend would be partly linked to our environment, with around 20% of cancers stemming from exposure to environmental contaminants, notably chemicals like polycyclic aromatic hydrocarbons (PAHs). PAHs are widespread pollutants in our environment resulting from incomplete combustion or pyrolysis of organic material, and thus produced by both natural and anthropic sources; notably benzo[a]pyrene (B[a]P), i.e. the prototypical molecule of this family, that can be detected in cigarette smoke, diesel exhaust particles, occupational-related fumes, and grilled food. This molecule is a well-recognized carcinogen belonging to group 1 carcinogens. Indeed, it can target the different steps of the carcinogenic process and all cancer hallmarks. Interestingly, H+ dynamics have been described as key parameters for the occurrence of several, if not all, of these hallmarks. However, information regarding the role of such parameters during environmental carcinogenesis is still very scarce. The present review will thus mainly give an overview of the impact of B[a]P on H+ dynamics in liver cells, and will show how such alterations might impact different aspects related to the finely-tuned balance between cell death and survival processes, thereby likely favoring environmental carcinogenesis. In total, the main objective of this review is to encourage further research in this poorly explored field of environmental molecular toxicology.
Published: 2019

33. Zebrafish larva as a reliable model forin vivoassessment of membrane remodeling involvement in the hepatotoxicity of chemical agents

Author: Odile Sergent, Morgane Fernier, Doris Cassio, Dominique Lagadic-Gossmann, Olivier Kah, Normand Podechard, Martine Chevanne, Aurore Collin, and Arnaud Tête
Subjects: 0301 basic medicine, Liver injury, Context (language use), Pharmacology, Biology, Toxicology, medicine.disease, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, medicine.anatomical_structure, chemistry, In vivo, Hepatocyte, Membrane fluidity, medicine, Hepatic stellate cell, Lipid raft, Toxicant
Abstract: The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1-week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF-B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical-induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical-induced liver diseases. Copyright © 2016 John Wiley & Sons, Ltd.
Published: 2016

34. Membrane Remodeling as a Key Player of the Hepatotoxicity Induced by Co-Exposure to Benzo[a]pyrene and Ethanol of Obese Zebrafish Larvae

Author: Podechard, Muhammad Imran, Odile Sergent, Arnaud Tête, Isabelle Gallais, Martine Chevanne, Dominique Lagadic-Gossmann, and Normand
Subjects: membrane remodeling, lipid raft, zebrafish larva, high-fat diet, liver steatosis, steatohepatitis, co-exposure, ethanol, benzo[a]pyrene, pravastatin
Abstract: The rise in prevalence of non-alcoholic fatty liver disease (NAFLD) constitutes an important public health concern worldwide. Including obesity, numerous risk factors of NAFLD such as benzo[a]pyrene (B[a]P) and ethanol have been identified as modifying the physicochemical properties of the plasma membrane in vitro thus causing membrane remodeling—changes in membrane fluidity and lipid-raft characteristics. In this study, the possible involvement of membrane remodeling in the in vivo progression of steatosis to a steatohepatitis-like state upon co-exposure to B[a]P and ethanol was tested in obese zebrafish larvae. Larvae bearing steatosis as the result of a high-fat diet were exposed to ethanol and/or B[a]P for seven days at low concentrations coherent with human exposure in order to elicit hepatotoxicity. In this condition, the toxicant co-exposure raised global membrane order with higher lipid-raft clustering in the plasma membrane of liver cells, as evaluated by staining with the fluoroprobe di-4-ANEPPDHQ. Involvement of this membrane’s remodeling was finally explored by using the lipid-raft disruptor pravastatin that counteracted the effects of toxicant co-exposure both on membrane remodeling and toxicity. Overall, it can be concluded that B[a]P/ethanol co-exposure can induce in vivo hepatotoxicity via membrane remodeling which could be considered as a good target mechanism for developing combination therapy to deal with steatohepatitis.
Published: 2018
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35. ATPase inhibitory factor 1 (IF1): a novel player in pollutant-related diseases?

Author: Dominique Lagadic-Gossmann, Kévin Hardonnière, 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), UL, Université Laval, ANR-13-CESA-0009, Inserm, Institut National de la Santé et de la Recherche Médicale, RRA, National Radio Research Agency, 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 ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique(2013)
Subjects: 0301 basic medicine, Cell physiology, Cell death, Context (language use), Mitochondrion, Biology, Toxicology, medicine.disease_cause, Cell survival, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, F0F1-ATPase, Obesity, Mode of action, Cancer, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Environmental Carcinogen, Diabetes, Metabolic reprogramming, Environmental diseases, 3. Good health, Cell biology, IF1, Mitochondria, Benzo[a]pyrene, 030104 developmental biology, Cardiovascular diseases, Benzo(a)pyrene, chemistry, Carcinogenesis, Reprogramming, 030217 neurology & neurosurgery
Abstract: International audience; As reported by the World Health Organization, at least 20% of all cancers would be due to environmental agents. However, besides the genotoxic effects of these agents, other cellular and molecular mechanisms would also be involved. In this context, there is still a need to further decipher their precise mode of action. Our previous work showed that the environmental carcinogen benzo[a]pyrene (B[a]P), the prototype molecule of polycyclic aromatic hydrocarbons (PAHs), elicited a Warburg-like metabolic reprogramming responsible for signaling of cell survival. We next evidenced that the ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of the F0F1ATPase, was involved in this B[a]P-induced glycolytic reprogramming in liver cells, hence identifying IF1 as a new target for PAHs. This latter study has thus provided new insights about how environmental pollutants might contribute to related carcinogenesis, thereby paving the way for future research on largely disregarded aspects when analyzing the impact of environmental carcinogens. This prospective review will therefore focus on IF1, considering it as a potential new target for environmental toxicants. Indeed, this key peptide might serve as a “gateway” for these compounds to interfere with cell physiology, especially at the mitochondrial level, thereby possibly leading to development of a panel of pathologies in which IF1 could be implicated. © 2017 Elsevier B.V.
Published: 2018

36. Contributors

Author: Annayya R. Aroor, Jordan J. Bartlett, Amine Belaid, Delphine Benarroch-Popivker, Patrick Brest, Michael A. Brown, Donny M. Camera, Feng Cao, Asli F. Ceylan, Abderrahman Chargui, Jing-Hai Chen, Guillemette Crépeaux, Taixing Cui, Dao-Fu Dai, Marie Angela Domdom, Harilaos Filippakis, Romain K. Gherardi, Thomas G. Gillette, Eric Gilson, Jordi Gracia-Sancho, Iris Grosjean, Sergi Guixé-Muntet, Ying Han, Ting He, Paul Hofman, Xin-Yang Hu, Guanghong Jia, Dominique Lagadic-Gossmann, Linsen Li, Jianjun Lv, Xi Ma, Sai Ma, Jipeng Ma, Kenneth Maiese, Alina Maloyan, Mickael Meyer, Chao-Yu Miao, Shigeki Miyamoto, Baharia Mograbi, Amy M. Navratil, Ida Perrotta, Thomas Pulinilkunnil, Peter S. Rabinovitch, Jun Ren, Brian Rodrigues, Barnabé Roméo, Michael N. Sack, William J. Smiles, James R. Sowers, Dondong Sun, Yong Sun, Valerie P. Tan, Yao-Liang Tang, Purvi C. Trivedi, Xuejun Wang, Chen Wang, Jian’an Wang, Pei Wang, Shuyi Wang, Lu Wang, Xu-Dong Wang, Zhao V. Wang, Chang-Chen Xiao, Zhi Yang, Mingjie Yang, Lifang Yang, Jian Yang, Nathalie Yazbeck, Hong Yu, Yingmei Zhang, Qing Zhong, and Wei Zhu
Published: 2018

37. Lipophilic chemicals from diesel exhaust particles trigger calcium response in human endothelial cells via aryl hydrocarbon receptor non-genomic signalling

Author: Eric Le Ferrec, Bendik Christian Brinchmann, Klara Kukowski, Aubin Penna, Johan Øvrevik, Alena Kubátová, Dominique Lagadic-Gossmann, Jørn A. Holme, Kenji F. Shoji, Normand Podechard, University of Oslo (UiO), Norwegian Institute of Public Health [Oslo] (NIPH), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), University of North Dakota [Grand Forks] (UND), 228143, Norges Forskningsråd, Jonchère, Laurent, 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: 0301 basic medicine, genetic structures, Calcium in biology, lcsh:Chemistry, 0302 clinical medicine, Polycyclic Aromatic Hydrocarbons, lcsh:QH301-705.5, diesel exhaust particle extracts, endothelial cells, calcium signalling, membrane microdomains, aryl hydrocarbon receptor, Spectroscopy, ComputingMilieux_MISCELLANEOUS, Calcium signaling, Vehicle Emissions, Air Pollutants, biology, Chemistry, General Medicine, Store-operated calcium entry, Computer Science Applications, Membrane, 030220 oncology & carcinogenesis, Intracellular, chemistry.chemical_element, Calcium, complex mixtures, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Extracellular, Humans, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Calcium Signaling, Physical and Theoretical Chemistry, Molecular Biology, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Organic Chemistry, Aryl hydrocarbon receptor, Atherosclerosis, eye diseases, 030104 developmental biology, Receptors, Aryl Hydrocarbon, lcsh:Biology (General), lcsh:QD1-999, biology.protein, Biophysics, sense organs
Abstract: Exposure to diesel exhaust particles (DEPs) affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca2+]i is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM) on [Ca2+]i and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with n-hexane (n-Hex-EOM), dichloromethane (DCM-EOM), methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the n-Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in n-Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1) using micro-spectrofluorometry. The lipophilic n-Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca2+]i increases in HMEC-1. n-Hex-EOM triggered [Ca2+]i increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE). By contrast, the less lipophilic DCM-EOM triggered [Ca2+]i increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE). Both extracts increased [Ca2+]i via aryl hydrocarbon receptor (AhR) non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca2+]i increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by n-hexane and DCM seem to induce rapid AhR-dependent [Ca2+]i increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction extracted by DCM also caused an AhR-dependent reduction in global membrane order, which appeared to be connected to the [Ca2+]i increase.
Published: 2018

38. Mechanisms involved in the death of steatotic WIF-B9 hepatocytes co-exposed to benzo[a]pyrene and ethanol a possible key role for xenobiotic metabolism and nitric oxide

Author: Lydie Sparfel, Agnès Burel, Muhammad Imran, Marie Liamin, Dominique Lagadic-Gossmann, Arnaud Tête, Isabelle Gallais, Martine Chevanne, Simon Bucher, Nathalie Grova, Normand Podechard, Brice M.R. Appenzeller, Odile Sergent, Bernard Fromenty, 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Luxembourg Institute of Health (LIH), This work was supported by ANR [STEATOX project, 'ANR-13-CESA-0009']., ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique(2013), 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 Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], CYP1A1, Apoptosis, Biochemistry, Benzoates, chemistry.chemical_compound, 0302 clinical medicine, Superoxides, Basic Helix-Loop-Helix Transcription Factors, Superoxide, Fatty Acids, Imidazoles, NF-kappa B, Cell biology, Benzo(a)pyrene, 030220 oncology & carcinogenesis, Peroxynitrite, Intracellular, Signal Transduction, Programmed cell death, DNA damage, Metalloporphyrins, Nitric Oxide, liver, Nitric oxide, 03 medical and health sciences, Necrosis, Physiology (medical), Cell Line, Tumor, NAFLD, Cytochrome P-450 CYP1A1, Animals, Carcinogen, Ethanol, Chimera, AhR, Alcohol Dehydrogenase, Fibroblasts, Rats, 030104 developmental biology, chemistry, Gene Expression Regulation, Receptors, Aryl Hydrocarbon, Hepatocytes, Pyrazoles, ADH, Azo Compounds, peroxynitrite anion
Abstract: International audience; We previously demonstrated that co-exposing pre-steatotic hepatocytes to benzo[a]pyrene (B[a]P), a carcinogenic environmental pollutant, and ethanol, favored cell death. Here, the intracellular mechanisms underlying this toxicity were studied. Steatotic WIF-B9 hepatocytes, obtained by a 48h-supplementation with fatty acids, were then exposed to B[a]P/ethanol (10nM/5mM, respectively) for 5 days. Nitric oxide (NO) was demonstrated to be a pivotal player in the cell death caused by the co-exposure in steatotic hepatocytes. Indeed, by scavenging NO, CPTIO treatment of co-exposed steatotic cells prevented not only the increase in DNA damage and cell death, but also the decrease in the activity of CYP1, major cytochrome P450s of B[a]P metabolism. This would then lead to an elevation of B[a]P levels, thus possibly suggesting a long-lasting stimulation of the transcription factor AhR. Besides, as NO can react with superoxide anion to produce peroxynitrite, a highly oxidative compound, the use of FeTPPS to inhibit its formation indicated its participation in DNA damage and cell death, further highlighting the important role of NO. Finally, a possible key role for AhR was pointed out by using its antagonist, CH-223191. Indeed it prevented the elevation of ADH activity, known to participate to the ethanol production of ROS, notably superoxide anion. The transcription factor, NFκB, known to be activated by ROS, was shown to be involved in the increase in iNOS expression. Altogether, these data strongly suggested cooperative mechanistic interactions between B[a]P via AhR and ethanol via ROS production, to favor cell death in the context of prior steatosis.
Published: 2018

39. Possible Involvement of Mitochondrial Dysfunction and Oxidative Stress in a Cellular Model of NAFLD Progression Induced by Benzo[a]pyrene/Ethanol CoExposure

Author: Grégory Pinon, Dominique Lagadic-Gossmann, Karima Begriche, Simon Bucher, Dounia Le Guillou, Arnaud Tête, Julien Allard, Odile Sergent, Bernard Fromenty, Jonchère, Laurent, Contaminants et Environnements : Santé, Adaptabilité, Comportements et Usages - Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique - - STEATOX2013 - ANR-13-CESA-0009 - CESA - VALID, Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École des Hautes Études en Santé Publique [EHESP] (EHESP), 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 ), Region Bretagne (ARED), Agence Nationale de la Recherche (ANR), ANR [ANR-13-CESA-0009], Institut National de la Sante et de la Recherche Medicale (INSERM), ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique(2013), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), 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: 0301 basic medicine, Aging, [SDV]Life Sciences [q-bio], Respiratory chain, medicine.disease_cause, Biochemistry, chemistry.chemical_compound, Non-alcoholic Fatty Liver Disease, ob/ob mice, Beta oxidation, chemistry.chemical_classification, biology, lcsh:Cytology, Chemistry, Fatty liver, respiratory-chain, General Medicine, 3. Good health, Mitochondria, heparg cells, [SDV] Life Sciences [q-bio], fatty liver-disease, aryl-hydrocarbon receptor, human hepatocytes, beta-oxidation, up-regulation, complex ii, in-vitro, Mitochondrial respiratory chain, Benzo(a)pyrene, Disease Progression, Research Article, medicine.medical_specialty, Article Subject, 03 medical and health sciences, Internal medicine, medicine, Humans, lcsh:QH573-671, Reactive oxygen species, Ethanol, Cell Biology, Aryl hydrocarbon receptor, medicine.disease, Oxidative Stress, 030104 developmental biology, Endocrinology, biology.protein, Oxidative stress
Abstract: International audience; Exposure to xenobiotics could favor the transition of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis in obese patients. Recently, we showed in different models of NAFL that benzo[a]pyrene (B[a]P) and ethanol coexposure induced a steatohepatitis-like state. One model was HepaRG cells incubated with stearate and oleate for 2 weeks. In the present study, we wished to determine in this model whether mitochondrial dysfunction and reactive oxygen species (ROS) overproduction could be involved in the occurrence of this steatohepatitis-like state. CRISPR/Cas9-modified cells were also used to specify the role of aryl hydrocarbon receptor (AhR), which is potently activated by B[a]P. Thus, nonsteatotic and steatotic HepaRG cells were treated with B[a]P, ethanol, or both molecules for 2 weeks. B[a]P/ethanol coexposure reduced mitochondrial respiratory chain activity, mitochondrial respiration, and mitochondrial DNA levels and induced ROS overproduction in steatotic HepaRG cells. These deleterious effects were less marked or absent in steatotic cells treated with B[a]P alone or ethanol alone and in nonsteatotic cells treated with B[a]P/ethanol. Our study also disclosed that B[a]P/ ethanol-induced impairment of mitochondrial respiration was dependent on AhR activation. Hence, mitochondrial dysfunction and ROS generation could explain the occurrence of a steatohepatitis-like state in steatotic HepaRG cells exposed to B[a]P and ethanol.
Published: 2018

40. Nrf2 and AhR in metabolic reprogramming after contaminant exposure

Author: Elisa Boutet-Robinet, Laurence Huc, Dominique Lagadic-Gossmann, Sylvie Bortoli, Chard-Hutchinson, Xavier, PROGRAMME DE RECHERCHE EN ALIMENTATION ET INDUSTRIES ALIMENTAIRES - Stratégies préventives de la cancérogenèse colorectale en production et transformation des viandes - - SECURIVIANDE2010 - ANR-10-ALIA-0014 - ALIA - VALID, ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, 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 ), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The authors are supported by grants: ITMO Cancer AVIESAN within the framework of the Cancer Plan for METAhCOL (n°17CE041) (SB, EBR, DLG and LH) for NeoMeaTox (n° ENV201213)(LH), for ONCOMETABOTOX (n°P027395) and ANR ALIA SecuriViande (ANR-10-ALIA-14) (LHL)., ANR-10-ALIA-0014,SECURIVIANDE,Stratégies préventives de la cancérogenèse colorectale en production et transformation des viandes(2010), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), 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 ), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Huc, Laurence
Subjects: 0301 basic medicine, Cell, Biology, Toxicology, Nrf2, 03 medical and health sciences, chemistry.chemical_compound, Detoxification, medicine, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, detoxification, Transcription factor, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, environmental carcinogenesis, AhR, Metabolic reprogramming, Metabolism, respiratory system, Cell biology, 030104 developmental biology, medicine.anatomical_structure, chemistry, Environmental Carcinogenesis, Xenobiotic, Reprogramming, Toxicant
Abstract: International audience; Beside their crucial role in xenobiotic biotransformation, AhR and Nrf2 are involved in the regulation of energetic metabolism. Nrf2, as a cytoprotective transcription factor, supply energy for detoxification and antioxidant response. AhR is ligand-activated transcriptional factor implicated in several physiological function. Following pollutant exposure, it acts as a chemosensor to eliminate harmful chemicals. Altogether, AhR and Nrf2 cooperate to contribute to protective responses upon contaminant exposure, including metabolic remodelling. This fine-tuned energetic coupling with detoxification can lead to prominent dysfunction under a chronic exposure to pollutants, and promote a long-term reprogramming that affects multiple cellular activities. In the article, we review the involvement of Nrf2 and AhR in the metabolic adaptations that occur during the short-term cell defence upon toxicant exposure, and in the metabolic reprogramming caused by their sustained activation. We also provide several clues to highlight the potential role of the Nrf2/AhR-induced metabolic changes in environmental carcinogenesis. © 2017
Published: 2018

41. Evidence of selective activation of aryl hydrocarbon receptor nongenomic calcium signaling by pyrene

Author: Isabelle Gallais, Eric Le Ferrec, Bendik Christian Brinchmann, Jørn A. Holme, Henrik S. Huitfeldt, William H. Bisson, Johan Øvrevik, Normand Podechard, Dominique Lagadic-Gossmann, Odile Sergent, Norwegian Institute of Public Health [Oslo] (NIPH), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Oregon State University (OSU), Oslo University Hospital [Oslo], 228143, Norges Forskningsråd, Université de Rennes 1, 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 Chard-Hutchinson, Xavier
Subjects: 0301 basic medicine, Aryl hydrocarbon receptor nuclear translocator, Indoles, Endothelial cells, Biochemistry, Protein Structure, Secondary, 03 medical and health sciences, chemistry.chemical_compound, Basic Helix-Loop-Helix Transcription Factors, Humans, Calcium Signaling, Transcription factor, Membrane remodelling, ComputingMilieux_MISCELLANEOUS, Aryl hydrocarbon receptor, Calcium signaling, Pharmacology, Binding Sites, Pyrenes, biology, HEK 293 cells, respiratory system, Store-operated calcium entry, Polycyclic aromatic hydrocarbons, Cell biology, Molecular Docking Simulation, [SDV.TOX] Life Sciences [q-bio]/Toxicology, 030104 developmental biology, HEK293 Cells, chemistry, Receptors, Aryl Hydrocarbon, Purines, [SDV.TOX]Life Sciences [q-bio]/Toxicology, biology.protein, Pyrene, Pyrazoles, Calcium, Azo Compounds, Intracellular
Abstract: In its classical genomic mode of action, the aryl hydrocarbon receptor (AhR) acts as a ligand activated transcription factor regulating expression of target genes such as CYP1A1 and CYP1B1. Some ligands may also trigger more rapid nongenomic responses through AhR, including calcium signaling (Ca2+). In the present study we observed that pyrene induced a relatively rapid increase in intracellular Ca2+-concentrations ([Ca2+]i) in human microvascular endothelial cells (HMEC-1) and human embryonic kidney cells (HEK293) that was attenuated by AhR-inhibitor treatment and/or transient AhR knockdown by RNAi. In silico molecular docking based on homology models, suggested that pyrene is not able to bind to the human AhR in the agonist conformation. Instead, pyrene docked in the antagonist conformation of the AhR PAS-B binding pocket, although the interaction differed from antagonists such as GNF-351 and CH223191. Accordingly, pyrene did not induce CYP1A1 or CYP1B1, but suppressed CYP1-expression by benzo[a]pyrene (B[a]P) in HMEC-1 cells, confirming that pyrene act as an antagonist of AhR-induced gene expression. Use of pharmacological inhibitors and Ca2+-free medium indicated that the pyrene-induced AhR nongenomic [Ca2+]i increase was initiated by Ca2+-release from intracellular stores followed by a later phase of extracellular Ca2+-influx, consistent with store operated calcium entry (SOCE). These effects was accompanied by an AhR-dependent reduction in ordered membrane lipid domains, as determined by di-4-ANEPPDHQ staining. Addition of cholesterol inhibited both the pyrene-induced [Ca2+]i-increase and alterations in membrane lipid order. In conclusion, we propose that pyrene binds to AhR, act as an antagonist of the canonical genomic AhR/Arnt/CYP1-pathway, reduces ordered membrane lipid domains, and activates AhR nongenomic Ca2+-signaling from intracellular stores.
Published: 2018

42. Autophagy-Driven Cancer Drug Development

Author: Abderrahman Chargui, Dominique Lagadic-Gossmann, Iris Grosjean, Mickael Meyer, Nathalie Yazbeck, Eric Gilson, Marie Angela Domdom, Barnabé Roméo, Harilaos Filippakis, Patrick Brest, Baharia Mograbi, Delphine Benarroch-Popivker, Guillemette Crépeaux, Paul Hofman, Amine Belaid, and Romain K. Gherardi
Subjects: 0301 basic medicine, business.industry, Autophagy, Cancer drugs, Cancer therapy, Cancer, Tumor initiation, medicine.disease, Metastasis, law.invention, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, law, 030220 oncology & carcinogenesis, Signaling proteins, Cancer research, Medicine, Suppressor, business
Abstract: Survival rates of patients with metastatic or recurrent cancers have remained virtually unchanged during the past 30 years. This fact makes the need for new therapeutic options even more urgent. An attractive option would be to target autophagy, an essential quality control process that degrades toxic aggregates, damaged organelles, and signaling proteins, and acts as a tumor suppressor pathway of tumor initiation. Conversely, other fascinating observations suggest that autophagy supports cancer progression, relapse, metastasis, dormancy, and resistance to therapy. This chapter provides an overview of the contradictory roles that autophagy plays in cancer initiation and progression and discusses the promises and challenges of current strategies that target autophagy for cancer therapy.
Published: 2018

43. Editorial overview Metabolic disruption in environmental diseases

Author: Rodrigo Franco-Cruz, Dominique Lagadic-Gossmann, University of Nebraska [Lincoln], University of Nebraska System, 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 ), University of Nebraska–Lincoln, 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: [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, 0303 health sciences, 03 medical and health sciences, 010501 environmental sciences, Toxicology, 01 natural sciences, ComputingMilieux_MISCELLANEOUS, 3. Good health, 030304 developmental biology, 0105 earth and related environmental sciences
Abstract: International audience; [No abstract available]
Published: 2018

44. Membrane remodeling by polycyclic aromatic hydrocarbons and its role in cell death signalling

Author: Dominique Lagadic-Gossmann, 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: [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Signalling, Biochemistry, Chemistry, Membrane remodeling, General Medicine, Toxicology, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2017

45. Environmental carcinogenesis and pH homeostasis: Not only a matter of dysregulated metabolism

Author: Laurence Huc, Dominique Lagadic-Gossmann, Jørn A. Holme, Kévin Hardonnière, Odile Sergent, 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 ), Contaminants & Stress Cellulaire (ToxAlim-COMICS), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT), Division of Environmental Medicine, Norwegian Institute of Public Health [Oslo] (NIPH), This work was financially supported by the French Ministry of Research, Région Bretagne, the Ligue contre le Cancer, and the French National Agency for Research (ANR, STEATOX project: ANR-13-CESA-0009)., ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique(2013), Jonchère, Laurent, Contaminants et Environnements : Santé, Adaptabilité, Comportements et Usages - Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique - - STEATOX2013 - ANR-13-CESA-0009 - CESA - VALID, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, 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 ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, Cancer Research, Programmed cell death, Carcinogenesis, Regulator, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Na+/H+ exchanger, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Homeostasis, Humans, Carcinogen, Cancer, Environmental Exposure, Hydrogen-Ion Concentration, medicine.disease, Warburg effect, 3. Good health, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Benzo[a]pyrene, 030104 developmental biology, pH and carcinogenesis, Biochemistry, Benzo(a)pyrene, chemistry, 030220 oncology & carcinogenesis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Environmental Carcinogenesis, Carcinogens, Cancer research
Abstract: International audience; According to the World Health Organization, around 20% of all cancers would be due to environmental factors. Among these factors, several chemicals are indeed well recognized carcinogens. The widespread contaminant benzo[a]pyrene (B[a]P), an often used model carcinogen of the polycyclic aromatic hydrocarbons' family, has been suggested to target most, if not all, cancer hallmarks described by Hanahan and Weinberg. It is classified as a group I carcinogen by the International Agency for Research on Cancer; however, the precise intracellular mechanisms underlying its carcinogenic properties remain yet to be thoroughly defined. Recently, the pH homeostasis, a well known regulator of carcinogenic processes, was suggested to be a key actor in both cell death and Warburg-like metabolic reprogramming induced upon B[a]P exposure. The present review will highlight those data with the aim of favoring research on the role of H + dynamics in environmental carcinogenesis.
Published: 2017

46. Effect of the co-exposure of benzo[a]pyrene with ethanol on the progression of fatty liver disease

Author: Isabelle Gallais, Dominique Lagadic-Gossmann, Odile Sergent, Martine Chevanne, Arnaud Tête, 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: [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, medicine.medical_specialty, Ethanol, Chemistry, Fatty liver, General Medicine, Toxicology, medicine.disease, 3. Good health, chemistry.chemical_compound, Endocrinology, Benzo(a)pyrene, Internal medicine, medicine, Co exposure, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2017

47. SAT-403-Polycyclic aromatic hydrocarbons can trigger a hepatocyte release of cytotoxic extracellular vesicles

Author: Isabelle Gallais, Agnès Burel, Dominique Lagadic-Gossmann, Nettie van Meteren, Odile Sergent, Soizic Chevance, Fabienne Gauffre, Martine Chevanne, and Eric Le Ferree
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Hepatology, Chemistry, Hepatocyte, medicine, Cytotoxic T cell, 030211 gastroenterology & hepatology, Extracellular vesicles, 030304 developmental biology, Cell biology
Published: 2019

48. 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

49. The cleaved FAS ligand activates the Na+/H+ exchanger NHE1 through Akt/ROCK1 to stimulate cell motility

Author: Patrick Legembre, Sébastien Tauzin, Dominique Lagadic-Gossmann, Michael Monet, Laurent Counillon, Mallorie Poët, Auréa Cophignon, Pierre Vacher, Amélie Fouqué, Laboratoire de PhysioMédecine Moléculaire (LP2M), 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)-Université Côte d'Azur (UCA), Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by CNRS and the University of Nice-Sophia Antipolis, the ICST Labex, grants from INCa PLBIOL, Ligue Contre le Cancer (Comités d’Ille-et-Vilaine/du Morbihan/des Côtes d’Armor/du Maine et Loire), ARC, Région Bretagne, Rennes Métropole., Université Nice Sophia Antipolis (1965 - 2019) (UNS), 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 de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), and Jonchère, Laurent
Subjects: 0301 basic medicine, Fas Ligand Protein, RHOA, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Fas ligand, Cell Line, Metastasis, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Humans, ROCK1, Cell migration, Phosphorylation, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, ComputingMilieux_MISCELLANEOUS, rho-Associated Kinases, Sodium-Hydrogen Exchanger 1, Multidisciplinary, biology, Fas receptor, Cell biology, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Protons, Signal transduction, rhoA GTP-Binding Protein, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract: Transmembrane CD95L (Fas ligand) can be cleaved to release a promigratory soluble ligand, cl-CD95L, which can contribute to chronic inflammation and cancer cell dissemination. The motility signaling pathway elicited by cl-CD95L remains poorly defined. Here, we show that in the presence of cl-CD95L, CD95 activates the Akt and RhoA signaling pathways, which together orchestrate an allosteric activation of the Na+/H+ exchanger NHE1. Pharmacologic inhibition of Akt or ROCK1 independently blocks the cl-CD95L-induced migration. Confirming these pharmacologic data, disruption of the Akt and ROCK1 phosphorylation sites on NHE1 decreases cell migration in cells exposed to cl-CD95L. Together, these findings demonstrate that NHE1 is a novel molecular actor in the CD95 signaling pathway that drives the cl-CD95L-induced cell migration through both the Akt and RhoA signaling pathways.
Published: 2016

50. The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival

Author: Elise Saunier, Florence Habarou, Baharia Mograbi, Chantal Benelli, Odile Sergent, Marie-Thérèse Lavault, Paule Bénit, Laurence Huc, Morgane Fernier, Kévin Hardonnière, Chris Ottolenghi, Maxime Janin, Anthony Lemarié, Pierre Rustin, Samantha Antonio, Isabelle Gallais, Sylvie Bortoli, Cécile Héliès-Toussaint, Dominique Lagadic-Gossmann, 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 ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine, Université Paris Diderot - Paris 7 (UPD7), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de Biochimie Métabolique, CHU Necker - Enfants Malades [AP-HP], Plateforme microscopie électronique, MRic Campus Santé, Rennes 1, France, French Ministry for Education and Research, Faculte des Sciences Pharmaceutiques et Biologiques de Rennes (University of Rennes 1), Region Provence Alpes Cote d'Azur, Agence regionale sante Provence Alpes Cote d'Azur, Direction regionale de l'Environnement, de l'amenagement et du logement Provence Alpes Cote d'Azur [6.3.3.3, 6.3.3.4], Universite Paris Descartes, Ligue contre le cancer [22,35,49,85], French National Academy of Medicine, ANR [ANR-13-CESA-0009], ITMO Cancer AVIESAN (National Alliance for Life Sciences and Health) within the framework of the Cancer Plan, Association for Cancer Research (ARC, CANC'AIR Genexposomic project), ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique(2013), Jonchère, Laurent, Contaminants et Environnements : Santé, Adaptabilité, Comportements et Usages - Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique - - STEATOX2013 - ANR-13-CESA-0009 - CESA - VALID, 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 ), Prévention et promotion de la cancérogénèse par les aliments (ToxAlim-PPCA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Contaminants & Stress Cellulaire (ToxAlim-COMICS), Institut de recherche, 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 ) -Université des Antilles ( UA ), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), ToxAlim ( ToxAlim ), Institut National Polytechnique [Toulouse] ( INP ) -Institut National de la Recherche Agronomique ( INRA ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse ( ENVT ), Institut National Polytechnique de Toulouse ( INPT ) -Institut National Polytechnique de Toulouse ( INPT ), Université Nice Sophia Antipolis - Faculté de Médecine ( UNS UFR Médecine ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Institut de Recherche sur le Cancer et le Vieillissement ( IRCAN ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique ( 2013 ), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)
Subjects: 0301 basic medicine, Respiratory chain, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, chemistry.chemical_compound, 0302 clinical medicine, atp synthase, oxidative stress, mitochondrial-function, Sodium-Hydrogen Exchanger 1, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, respiratory-chain, hepa1c1c7 cells, hexokinase-ii, Cellular Reprogramming, Warburg effect, 3. Good health, Cell biology, Liver, Benzo(a)pyrene, 030220 oncology & carcinogenesis, Epithelial-Mesenchymal Transition, Cell Survival, Cellular respiration, Citric Acid Cycle, kappa-b, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Cell Line, [ SDV.EE.SANT ] Life Sciences [q-bio]/Ecology, environment/Health, 03 medical and health sciences, hepg2 cells, [SDV.CAN] Life Sciences [q-bio]/Cancer, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Animals, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Lactic Acid, Carcinogen, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, complex ii, Epithelial Cells, Membrane hyperpolarization, apoptosis induction, Carcinogens, Environmental, Rats, 030104 developmental biology, chemistry, Apoptosis, Cancer cell, Energy Metabolism, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).
Published: 2016

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