Ambolet-Camoit Ariane, Ottolenghi Chris, Leblanc Alix, Kim Min Ji, Letourneur Franck, Jacques Sébastien, Cagnard Nicolas, Guguen-Guillouzo Christiane, Barouki Robert, Aggerbeck Martine
Inserm UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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.
Biochimie. 2015 Sep;116:79-91. doi: 10.1016/j.biochi.2015.07.003. Epub 2015 Jul 6.
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.
通常情况下，个体暴露于环境中的外源性化学物质混合物中，这些混合物会影响多个器官，并通过不同的异源物质感受器和途径，以物种和细胞类型特异性的方式发挥作用。2,3,7,8 - 四氯二苯并 - p - 二恶英（TCDD）和α - 硫丹是持久性有机污染物（POPs）和内分泌干扰物，它们通过不同的异源物质感受器发挥作用，并在肝脏中蓄积。我们在这项HEALS研究中的目的是调查这些POPs混合物对人源肝细胞系HepaRG基因表达的影响。我们发现，尽管TCDD和α - 硫丹的作用在很大程度上不相关，但混合后会改变基因的表达。POPs混合物的联合作用显著改变了100个基因的表达（42个上调和58个下调），而单独使用相同浓度的任何一种POP都不会显著改变这些基因的表达。对于另外32个基因，观察到TCDD和α - 硫丹之间存在选择性抑制性串扰。混合物中的一种POP抑制了另一种对基因表达的影响，尽管单独使用时该POP不会影响表达。另外82个基因的表达被单一的POP显著改变（上调或下调）。添加第二种POP要么在相同方向上增强对基因表达的影响，要么没有进一步影响。在低浓度（0.2 nM TCDD和1 μM α - 硫丹）下，POPs仍然有显著影响，并且发现一些基因相应蛋白质的表达水平受到影响。特别显著的是，混合物对几种肝脏中间代谢途径（甘油脂质代谢、FXR/RXR激活、糖酵解/糖异生、类视黄醇和胆汁酸生物合成）的多个基因的表达有80 - 90%的抑制作用，而每种污染物单独作用时只有中等程度的影响。
