PUBLICATION
MEHP/ethanol co-exposure favors the death of steatotic hepatocytes, possibly through CYP4A and ADH involvement
- Authors
- Tête, A., Gallais, I., Imran, M., Legoff, L., Martin-Chouly, C., Sparfel, L., Bescher, M., Sergent, O., Podechard, N., Lagadic-Gossmann, D.
- ID
- ZDB-PUB-201007-10
- Date
- 2020
- Source
- Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 146: 111798 (Journal)
- Registered Authors
- Keywords
- AhR, DEHP, DNA damage, NAFLD, Zebrafish larvae, oxidative stress
- MeSH Terms
-
- Alcohol Dehydrogenase/metabolism*
- Animals
- Cell Death/drug effects*
- Cytochrome P-450 CYP4A/metabolism*
- Diethylhexyl Phthalate/analogs & derivatives*
- Diethylhexyl Phthalate/toxicity
- Ethanol/toxicity*
- Fatty Liver/pathology*
- Hepatocytes/drug effects*
- Humans
- PubMed
- 33022287 Full text @ Food Chem. Toxicol.
- CTD
- 33022287
Citation
Tête, A., Gallais, I., Imran, M., Legoff, L., Martin-Chouly, C., Sparfel, L., Bescher, M., Sergent, O., Podechard, N., Lagadic-Gossmann, D. (2020) 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. 146:111798.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping