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Toxicol In Vitro. 2017 Dec;45(Pt 3):309-317. doi: 10.1016/j.tiv.2017.06.029. Epub 2017 Jul 1.

Down-regulation of the expression of alcohol dehydrogenase 4 and CYP2E1 by the combination of α-endosulfan and dioxin in HepaRG human cells.

Author information

1
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.
2
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.
3
Proteomics platform, Barcelona Science Park, Barcelona, Spain.
4
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. Electronic address: etienne.blanc@parisdescartes.fr.

Abstract

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.

KEYWORDS:

ADH4; Liver; Organochlorine pesticide; Persistent organic pollutant; Pollutant mixture; TCDD

PMID:
28673560
DOI:
10.1016/j.tiv.2017.06.029
[Indexed for MEDLINE]

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