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

Alix F Leblanc; Eléonore A Attignon; Emilie Distel; Spyros P Karakitsios; Dimosthenis A Sarigiannis; Sylvie Bortoli; Robert Barouki; Xavier Coumoul; Martine Aggerbeck; Etienne B Blanc

doi:10.1016/j.envres.2019.108628

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

Environ Res. 2019 Nov:178:108628. doi: 10.1016/j.envres.2019.108628. Epub 2019 Aug 6.

Authors

Affiliations

¹ INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, 45 rue des Saints Pères, 75006, Paris, France; Université de Paris, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France. Electronic address: alix.leblanc@gmail.com.
² INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, 45 rue des Saints Pères, 75006, Paris, France; Université de Paris, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France. Electronic address: eleonore.attignon@hotmail.fr.
³ INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, 45 rue des Saints Pères, 75006, Paris, France; Université de Paris, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France. Electronic address: emilie.distel@gmail.com.
⁴ Aristotle University of Thessaloniki, Department of Chemical Engineering, 54 124, Thessaloniki, Greece. Electronic address: spyros.karakitsios@gmail.com.
⁵ Aristotle University of Thessaloniki, Department of Chemical Engineering, 54 124, Thessaloniki, Greece; Environmental Health Engineering, Institute for Advanced Study, Pavia, Italy. Electronic address: d.a.sarigiannis@gmail.com.
⁶ INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, 45 rue des Saints Pères, 75006, Paris, France; Université de Paris, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France. Electronic address: sylvie.bortoli@parisdescartes.fr.
⁷ INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, 45 rue des Saints Pères, 75006, Paris, France; Université de Paris, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France; AP-HP, Hôpital Necker-Enfants Malades, Service de Biochimie Métabolique, 149, rue de Sèvres, 75743, Paris, France. Electronic address: robert.barouki@parisdescartes.fr.
⁸ INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, 45 rue des Saints Pères, 75006, Paris, France; Université de Paris, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France. Electronic address: xavier.coumoul@parisdescartes.fr.
⁹ INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, 45 rue des Saints Pères, 75006, Paris, France; Université de Paris, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France. Electronic address: martine.aggerbeck@parisdescartes.fr.
¹⁰ INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, 45 rue des Saints Pères, 75006, Paris, France; Université de Paris, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France. Electronic address: etienne.blanc@parisdescartes.fr.

PMID: 31520823
DOI: 10.1016/j.envres.2019.108628

Abstract

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

Keywords: Alpha-endosulfan; Carbohydrate metabolism; Dioxin; Liver; Pesticide; Pollutant mixture.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carbohydrate Metabolism / drug effects*
Cell Line
Ecosystem
Environmental Pollutants / toxicity*
Hepatocytes
Humans
Polychlorinated Dibenzodioxins / toxicity
Toxicity Tests

Substances

Environmental Pollutants
Polychlorinated Dibenzodioxins