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Novel roles for AhR and ARNT in the regulation of alcohol dehydrogenases in human hepatic cells

  • Molecular Toxicology
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Abstract

The mechanisms by which pollutants participate in the development of diverse pathologies are not completely understood. The pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the AhR (aryl hydrocarbon receptor) signaling pathway. We previously showed that TCDD (25 nM, 30 h) decreased the expression of several alcohol metabolism enzymes (cytochrome P450 2E1, alcohol dehydrogenases ADH1, 4 and 6) in differentiated human hepatic cells (HepaRG). Here, we show that, as rapidly as 8 h after treatment (25 nM TCDD) ADH expression decreased 40 % (p < 0.05). ADH1 and 4 protein levels decreased 40 and 27 %, respectively (p < 0.05), after 72 h (25 nM TCDD). The protein half-lives were not modified by TCDD which suggests transcriptional regulation of expression. The AhR antagonist CH-223191 or AhR siRNA reduced the inhibitory effect of 25 nM TCDD on ADH1A, 4 and 6 expression 50–100 % (p < 0.05). The genomic pathway (via the AhR/ARNT complex) and not the non-genomic pathway involving c-SRC mediated these effects. Other AhR ligands (3-methylcholanthrene and PCB 126) decreased ADH1B, 4 and 6 mRNAs by more than 78 and 55 %, respectively (p < 0.01). TCDD also regulated the expression of ADH4 in the HepG2 human hepatic cell line, in primary human hepatocytes and in C57BL/6J mouse liver. In conclusion, activation of the AhR/ARNT signaling pathway by AhR ligands represents a novel mechanism for regulating the expression of ADHs. These effects may be implicated in the toxicity of AhR ligands as well as in the alteration of ethanol or retinol metabolism and may be associated further with higher risk of liver diseases or/and alcohol abuse disorders.

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Acknowledgments

This work was supported by the IREB association (Institut de Recherche scientifique sur les Boissons, 2015/03), the FRA (Fondation pour la Recherche en Alcoologie, 2016/02), the ANR (Agence Nationale de la Recherche), and the INCa (Institut National du Cancer, Caroline Duval, postdoctoral fellowship, CESA 201101), and Université Paris Descartes, MESR (Ministère de l’Enseignement Supérieur et de la Recherche) for the doctoral fellowships (Eléonore Attignon, Alix Leblanc). We thank Pr X. Coumoul for critical reading and Dr L. Aggerbeck for editing the manuscript.

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    1. INSERM, UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, F-75006, Paris, France

      Eléonore A. Attignon, Alix F. Leblanc, Béatrice Le-Grand, Caroline Duval, Martine Aggerbeck, Hélène Rouach & Etienne B. Blanc

    2. ComUE Sorbonne Paris Cité, Université Paris Descartes, CICB-Paris, 45 rue des Saints Pères, F-75006, Paris, France

      Eléonore A. Attignon, Alix F. Leblanc, Béatrice Le-Grand, Caroline Duval, Martine Aggerbeck, Hélène Rouach & Etienne B. Blanc

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    1. Eléonore A. Attignon
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    Correspondence to Etienne B. Blanc.

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    Eléonore A. Attignon and Alix F. Leblanc have contributed equally to this work.

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    Supplementary material 1 (DOCX 17 kb)

    204_2016_1700_MOESM2_ESM.eps

    Supplementary material 2 a: The viability of HepaRG cells exposed for 8 days to different concentrations of TCDD was evaluated by the WST-1 test. b: Quantitative real-time PCR analysis of ADH1B and ADH4 mRNA expression after 8 days of exposure to several concentrations of TCDD. * p < 0.05, ** p < 0.01, *** p < 0.001 (EPS 13747 kb)

    204_2016_1700_MOESM3_ESM.eps

    Supplementary material 3 The half-lives of ADH mRNAs are unchanged after exposure of cells to TCDD. The half-lives of ADH mRNAs, as measured by quantitative real-time PCR, in the presence of DRB, an inhibitor of RNA polymerase II, are shown for HepaRG cells exposed or not (Control) to TCDD. Cells were exposed or not to 25 nM TCDD for 20 h then DRB was added and cells were harvested at 0, 4, 8, 12 and 24 h. The means are shown and the error bars represent the SD of three independent experiments (EPS 5041 kb)

    204_2016_1700_MOESM4_ESM.eps

    Supplementary material 4 siRNAs reduce the expression of AhR, ARNT and c-SRC mRNAs. Differentiated HepaRG cells were transfected with siRNA directed against AhR, ARNT or SRC or scrambled (siC). Three days after, the cells were exposed or not to 25 nM TCDD for 24 h. The levels of AhR (a) ARNT (b) and c-SRC (c) and CYP1A1 (d) mRNAs were measured by qRT-PCR. Relative mRNA levels were calculated using siC value as the reference. The means are shown and the error bars represent the SD of four independent experiments. ** p < 0.01 *** p < 0.001 as compared to untreated and untransfected cells (EPS 17465 kb)

    Supplementary material 5 Oligonucleotide sequences of primers used for qRT-PCR (EPS 27807 kb)

    204_2016_1700_MOESM6_ESM.eps

    Supplementary material 6 Values (means and SD) used for Fig. 1b: qRT-PCR measurement of ADH (ADH1A, 1B, 4, 5 and 6) mRNA expression as a function of the concentration of TCDD (0–25 nM for 24 h) (n = 3-4), in differentiated HepaRG cells (EPS 3338 kb)

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    Attignon, E.A., Leblanc, A.F., Le-Grand, B. et al. Novel roles for AhR and ARNT in the regulation of alcohol dehydrogenases in human hepatic cells. Arch Toxicol 91, 313–324 (2017). https://doi.org/10.1007/s00204-016-1700-4

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