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Transcriptomic analysis in zebrafish larvae identifies iron-dependent mitochondrial dysfunction as a possible key event of NAFLD progression induced by benzo[a]pyrene/ethanol co-exposure

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is a worldwide epidemic for which environmental contaminants are increasingly recognized as important etiological factors. Among them, the combination of benzo[a]pyrene (B[a]P), a potent environmental carcinogen, with ethanol, was shown to induce the transition of steatosis toward steatohepatitis. However, the underlying mechanisms involved remain to be deciphered. In this context, we used high-fat diet fed zebrafish model, in which we previously observed progression of steatosis to a steatohepatitis-like state following a 7-day-co-exposure to 43 mM ethanol and 25 nM B[a]P. Transcriptomic analysis highlighted the potent role of mitochondrial dysfunction, alterations in heme and iron homeostasis, involvement of aryl hydrocarbon receptor (AhR) signaling, and oxidative stress. Most of these mRNA dysregulations were validated by RT-qPCR. Moreover, similar changes were observed using a human in vitro hepatocyte model, HepaRG cells. The mitochondria structural and functional alterations were confirmed by transmission electronic microscopy and Seahorse technology, respectively. Involvement of AhR signaling was evidenced by using in vivo an AhR antagonist, CH223191, and in vitro in AhR-knock-out HepaRG cells. Furthermore, as co-exposure was found to increase the levels of both heme and hemin, we investigated if mitochondrial iron could induce oxidative stress. We found that mitochondrial labile iron content was raised in toxicant-exposed larvae. This increase was prevented by the iron chelator, deferoxamine, which also inhibited liver co-exposure toxicity. Overall, these results suggest that the increase in mitochondrial iron content induced by B[a]P/ethanol co-exposure causes mitochondrial dysfunction that contributes to the pathological progression of NAFLD.

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Data availability

All transcriptomic data are available in our supplemental files.

Abbreviations

AhR:

Aryl hydrocarbon receptor

AhR-KO:

AhR knock out

AMEN:

Annotation, Mapping, Expression and Network suite of tools

ANOVA:

One-way analysis of variance

B[a]P:

Benzo[a]pyrene

CREEA:

Comité Rennais d’Ethique en matière d’Expérimentation Animale

DMSO:

Dimethyl sulfoxide

DPF:

Days post-fertilization

FA:

Fatty acids

FCCP:

Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone

GEO:

Expression Omnibus

GO:

Gene ontology

GOEA:

Gene ontology enrichment analysis

HES:

Hematoxylin-eosin-safranin

HFD:

High-fat diet

HO1:

Heme oxygenase 1

IARC:

International Agency for Research on Cancer

IPA:

Ingenuity pathway analysis

KEGG:

Kyoto Encyclopedia of Genes and Genomes

NADP:

Nicotinamide adenine dinucleotide phosphate

NAFLD:

Alcoholic fatty liver disease

NaN3 :

Sodium azide

NASH:

Non-alcoholic steatohepatitis

NOS:

Reactive nitrogen species

OCR:

Oxygen consumption rate

OXPHOS:

Oxidative phosphorylation

PAH:

Polycyclic aryl hydrocarbon

PBS:

Phosphate-buffered saline

PMT:

Photomultiplier tube

ROS:

Reactive oxygen species

SEM:

Standard error of the mean

T2DM:

Type 2 diabetes mellitus

TAFLD:

Toxicant-associated fatty liver diseases

TASH:

Toxicant-associated steatohepatitis

TCDD:

2,3,7,8-Tetrachlorodibenzo-p-dioxin

TEM:

Transmission electronic microscopy

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Acknowledgements

We first wish to thank the INRA-LPGP (Institut National de la Recherche Agronomique, Laboratoire de Physiologie et Génomique des Poissons, Rennes, France) for providing zebrafish eggs. We are also very grateful to MRiC and H2P2 platforms (UMS BIOSIT, Rennes, France), notably Stéphanie Dutertre (MRic) for confocal microscopic imagery, Alain Fautrel and Pascal Belaud (H2P2) for their help on histological staining, and finally Agnes Burel (MRiC) for her expertise on electron microscopy. We also wish to thank Dr Olivier Loréal (UMR 1241, Inserm, Rennes) for the fruitful discussion regarding iron homeostasis. We are also grateful to Dr Catherine Lavau for her writing assistance (Irset - Inserm UMR_S 1085, Rennes). Muhammad Imran was the recipient of a fellowship from the Higher Education Commission, Pakistan. Simon Bucher was recipient of fellowships from the Région Bretagne (ARED) and from the Agence Nationale de la Recherche (ANR). We also wish to thank ANR and the Institut Thématique Multi-Organisme Cancer (ITMO Cancer) d’Aviesan for financial supports to our work (STEATOX project, “ANR-13-CESA-0009,” and METAhCOL project, n°17CE040_00).

Funding

This work was supported by the Agence Nationale de la Recherche (ANR) and the Institut Thématique Multi-Organisme Cancer (ITMO Cancer) d’Aviesan (STEATOX project, “ANR-13-CESA-0009,” and METAhCOL project, n°17CE040_00).

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  1. Muhammad Imran

    Present address: Iqra University, Karachi, Pakistan

Authors and Affiliations

  1. Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé environnement et travail) – UMR_S 1085, F-35000, Rennes, France

    Muhammad Imran, Frédéric Chalmel, Odile Sergent, Bertrand Evrard, Hélène Le Mentec, Antoine Legrand, Maëlle Bescher, Lydie Sparfel, Dominique Lagadic-Gossmann & Normand Podechard

  2. Univ Rennes, Biosit – UMS 3480, US_S 018, F-35000, Rennes, France

    Aurélien Dupont

  3. Univ Rennes, Inserm, Inrae, Institut NUMECAN (Nutrition Metabolisms and Cancer)–UMR_S 13 1241, and UMR_A 1341, 35000, Rennes, France

    Simon Bucher & Bernard Fromenty

  4. Université de Toulouse, Inrae, ENVT, INP-Purpan, UPS, Toxalim (Research Centre in Food Toxicology), 31027, Toulouse, France

    Laurence Huc

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Contributions

Conception and design of the study (NP, MI, DLG, OS), acquisition of data (MI, FC, BE, HLM, AD, MB, SB, AL), analysis and interpretation of data (MI, NP, DLG, FC, LS, LH), and drafting the article or revising it critically for important intellectual content (MI, NP, DLG, OS, LS, BF, LH).

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Correspondence to Normand Podechard.

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All animal experiments were in agreement with the European Union regulations concerning the use and protection of experimental animals (Directive 2010/63/EU). All protocols were approved by the local ethics committee CREEA (Comité Rennais d’Ethique en matière d’Expérimentation Animale).

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Lydie  Sparfel, Dominique Lagadic-Gossmann, and Normand Podechard were co-last authors.

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Imran, M., Chalmel, F., Sergent, O. et al. Transcriptomic analysis in zebrafish larvae identifies iron-dependent mitochondrial dysfunction as a possible key event of NAFLD progression induced by benzo[a]pyrene/ethanol co-exposure. Cell Biol Toxicol 39, 371–390 (2023). https://doi.org/10.1007/s10565-022-09706-4

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