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

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.

Keywords: ADH4; Liver; Organochlorine pesticide; Persistent organic pollutant; Pollutant mixture; TCDD.

MeSH terms

  • Alcohol Dehydrogenase / biosynthesis*
  • Alcohol Dehydrogenase / drug effects
  • Cytochrome P-450 CYP2E1 / biosynthesis*
  • Cytochrome P-450 CYP2E1 / drug effects
  • Down-Regulation
  • Endosulfan / toxicity*
  • Environmental Pollutants / toxicity*
  • Hep G2 Cells
  • Humans
  • Insecticides / toxicity*
  • Polychlorinated Dibenzodioxins / toxicity*
  • RNA, Small Interfering
  • Receptors, Aryl Hydrocarbon / drug effects
  • Signal Transduction / drug effects


  • Environmental Pollutants
  • Insecticides
  • Polychlorinated Dibenzodioxins
  • RNA, Small Interfering
  • Receptors, Aryl Hydrocarbon
  • Alcohol Dehydrogenase
  • alcohol dehydrogenase IV
  • Cytochrome P-450 CYP2E1
  • Endosulfan