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 glucoReport as inadecuate




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 gluco - Download this document for free, or read online. Document in PDF available to download.

1 Toxicologie, Pharmacologie et Signalisation Cellulaire 2 AP-HP Hôpital Necker - Enfants Malades Paris 3 UPD5 - Université Paris Descartes - Paris 5 4 Foie, métabolismes et cancer

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 0.2nM TCDD and 1μM 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

Keywords : dioxin HepaRG metabolism microarray mixture Pesticides





Author: Ariane Ambolet-Camoit - Chris Ottolenghi - Alix Leblanc - Min Ji Kim - Franck Letourneur - Sébastien Jacques - Nicolas Cagnard -

Source: https://hal.archives-ouvertes.fr/



DOWNLOAD PDF




Related documents