MEHP/ethanol co-exposure favors the death of steatotic hepatocytes, possibly through CYP4A and ADH involvement.

Arnaud Tête, Isabelle Gallais, Muhammad Imran, Louis Legoff, Corinne Martin-Chouly, Lydie Sparfel, Maëlle Bescher, Odile Sergent, Normand Podechard, Dominique Lagadic-Gossmann

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2020 Dec

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Liver steatosis has been associated with various etiological factors (obesity, alcohol, environmental contaminants). How those factors work together to induce steatosis progression is still scarcely evaluated. Here, we tested whether phthalates could potentiate death of steatotic hepatocytes when combined with ethanol. Pre-steatotic WIF-B9 hepatocytes were co-exposed to mono (2-ethylhexyl) (MEHP, 500 nM; main metabolite of di (2-ethylhexyl) phthalate or DEHP) and ethanol (5 mM) for 5 days. An increased apoptotic death was detected, involving a DNA damage response. Using 4-Methypyrazole to inhibit ethanol metabolism, and CH-223191 to antagonize the AhR receptor, we found that an AhR-dependent increase in alcohol dehydrogenase (ADH) activity was essential for cell death upon MEHP/ethanol co-exposure. Toxicity was also prevented by HET0016 to inhibit the cytochrome P450 4A (CYP4A). Using the antioxidant thiourea, a role for oxidative stress was uncovered, notably triggering DNA damage. Finally, co-exposing the in vivo steatosis model of high fat diet (HFD)-zebrafish larvae to DEHP (2.56 nM)/ethanol (43 mM), induced the pathological progression of liver steatosis alongside an increased Cyp4t8 (human CYP4A homolog) mRNA expression. Altogether, these results further emphasized the deleterious impact of co-exposures to ethanol/environmental pollutant towards steatosis pathological progression, and unraveled a key role for ADH and CYP4A in such effects. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Arnaud Tête, Isabelle Gallais, Muhammad Imran, Louis Legoff, Corinne Martin-Chouly, Lydie Sparfel, Maëlle Bescher, Odile Sergent, Normand Podechard, Dominique Lagadic-Gossmann. MEHP/ethanol co-exposure favors the death of steatotic hepatocytes, possibly through CYP4A and ADH involvement. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2020 Dec;146:111798