INSERM UMR 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, 45 rue des Saints Pères, 75006 Paris, France.
INSERM UMR 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, 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.
Toxicol In Vitro. 2017 Dec;45(Pt 3):309-317. doi: 10.1016/j.tiv.2017.06.029. Epub 2017 Jul 1.
Pesticides and other persistent organic pollutants are considered as risk factors for liver diseases. We treated the human hepatic cell line HepaRG with both 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and the organochlorine pesticide, α-endosulfan, to evaluate their combined impact on the expression of hepatic genes involved in alcohol metabolism. We show that the combination of the two pollutants (25nM TCDD and 10μM α-endosulfan) led to marked decreases in the amounts of both the mRNA (up to 90%) and protein (up to 60%) of ADH4 and CYP2E1. Similar results were obtained following 24h or 8days of treatment with lower concentrations of these pollutants. Experiments with siRNA and AHR agonists and antagonist demonstrated that the genomic AHR/ARNT pathway is necessary for the dioxin effect. The PXR, CAR and estrogen receptor alpha transcription factors were not modulators of the effects of α-endosulfan, as assessed by siRNA transfection. In another human hepatic cell line, HepG2, TCDD decreased the expression of ADH4 and CYP2E1 mRNAs whereas α-endosulfan had no effect on these genes. Our results demonstrate that exposure to a mixture of pollutants may deregulate hepatic metabolism.
农药和其他持久性有机污染物被认为是肝脏疾病的风险因素。我们用 2,3,7,8 四氯二苯并对二恶英（TCDD）和有机氯农药α-硫丹处理人肝上皮细胞系 HepaRG，以评估它们对参与酒精代谢的肝基因表达的联合影响。我们表明，两种污染物（25nM TCDD 和 10μMα-硫丹）的组合导致 ADH4 和 CYP2E1 的 mRNA（高达 90%）和蛋白质（高达 60%）的含量明显下降。在较低浓度的这些污染物处理 24 小时或 8 天后也得到了类似的结果。用 siRNA 和 AHR 激动剂和拮抗剂进行的实验表明，基因组 AHR/ARNT 途径是 TCDD 作用所必需的。用 siRNA 转染评估，PXR、CAR 和雌激素受体α转录因子不是α-硫丹作用的调节剂。在另一种人肝上皮细胞系 HepG2 中，TCDD 降低 ADH4 和 CYP2E1 mRNA 的表达，而α-硫丹对这些基因没有影响。我们的结果表明，暴露于污染物混合物可能会使肝脏代谢失调。
