title: Two persistent organic pollutants which act through different xenosensors (alpha-endosulfan and 2,3,7,8 tetrachlorodibenzo-p-dioxin) interact in a mixture and downregulate multiple genes involved in human hepatocyte lipid and glucose metabolism.
abstract: Individuals, typically, are exposed to mixtures of environmental xenobiotics affecting multiple organs and acting through different xenosensors and pathways in species and cell-type specific manners. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and α-endosulfan are Persistent Organic Pollutants (POPs) and endocrine disruptors which act through different xenosensors and accumulate in the liver. Our objective in this HEALS study was to investigate the effects of the mixture of these POPs on gene expression in a human-derived hepatocyte cell line, HepaRG. We found that, in spite of having largely uncorrelated effects, TCDD and α-endosulfan, when mixed, alter the expression of genes. The combined effects of the mixture of the POPs significantly altered the expression of 100 genes (42 up- and 58 down-regulated) whereas the same concentration of either POP alone did not alter significantly the expression of these genes. For 32 other genes, selective inhibitory crosstalk between TCDD and α-endosulfan was observed. One of the POPs inhibited the effect, on gene expression, of the other in the mixture although, when used alone, that POP did not affect expression. The expression of another 82 genes was significantly altered (up- or down-regulated) by a single POP. The addition of the second POP either increased, in the same direction, the effect on gene expression or had no further effect. At low concentrations (0.2 nM TCDD and 1 μM α-endosulfan), the POPs still had significant effects and the levels of expression of the corresponding proteins were found to be affected for some genes. Particularly striking was the 80-90% inhibition, by the mixture, of the expression of a number of genes of several hepatic intermediary metabolic pathways (glycerolipid metabolism, FXR/RXR activation, glycolysis/gluconeogenesis, retinoid and bile acid biosynthesis), whereas each pollutant alone had only a moderate effect.
authors.affiliation: Inserm UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Ambolet-Camoit
authors.affiliation: Inserm UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; APHP, Hôpital Necker Enfants Malades, Service de Biochimie Métabolique, Paris, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.affiliation: Inserm UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Alix
authors.initials: A
authors.lastname: Leblanc
authors.affiliation: Inserm UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Plateforme de Génomique, Institut Cochin, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Letourneur
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Plateforme de Génomique, Institut Cochin, Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacques
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Plateforme de Génomique, Institut Cochin, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.affiliation: Université de Rennes 1, Rennes, France; Inserm, UMR991, Rennes, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Guguen-Guillouzo
authors.affiliation: Inserm UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; APHP, Hôpital Necker Enfants Malades, Service de Biochimie Métabolique, Paris, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Barouki
authors.affiliation: Inserm UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: martine.aggerbeck@parisdescartes.fr.
authors.forename: Martine
authors.initials: M
authors.lastname: Aggerbeck
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D004726:Endosulfan / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D005947:Glucose; D004726:Endosulfan
keywords: Dioxin; HepaRG; Metabolism; Microarray; Mixture; Pesticides