Integrated transcriptomics and metabolomics reveal signatures of lipid metabolism dysregulation in HepaRG liver cells exposed to PCB 126

Robin Mesnage,Theodoros Xenakis,Fabien Jourdan,Michael N Antoniou,Sucharitha Balu,Clément Frainay,Nathalie Poupin,Martina Biserni,Eva Wozniak,Charles A Mein

doi:10.1007/s00204-018-2235-7

Abstract

Chemical pollutant exposure is a risk factor contributing to the growing epidemic of non-alcoholic fatty liver disease (NAFLD) affecting human populations that consume a western diet. Although it is recognized that intoxication by chemical pollutants can lead to NAFLD, there is limited information available regarding the mechanism by which typical environmental levels of exposure can contribute to the onset of this disease. Here, we describe the alterations in gene expression profiles and metabolite levels in the human HepaRG liver cell line, a validated model for cellular steatosis, exposed to the polychlorinated biphenyl (PCB) 126, one of the most potent chemical pollutants that can induce NAFLD. Sparse partial least squares classification of the molecular profiles revealed that exposure to PCB 126 provoked a decrease in polyunsaturated fatty acids as well as an increase in sphingolipid levels, concomitant with a decrease in the activity of genes involved in lipid metabolism. This was associated with an increased oxidative stress reflected by marked disturbances in taurine metabolism. A gene ontology analysis showed hallmarks of an activation of the AhR receptor by dioxin-like compounds. These changes in metabolome and transcriptome profiles were observed even at the lowest concentration (100 pM) of PCB 126 tested. A decrease in docosatrienoate levels was the most sensitive biomarker. Overall, our integrated multi-omics analysis provides mechanistic insight into how this class of chemical pollutant can cause NAFLD. Our study lays the foundation for the development of molecular signatures of toxic effects of chemicals causing fatty liver diseases to move away from a chemical risk assessment based on in vivo animal experiments.

Highlights

A growing epidemic of non-alcoholic fatty liver disease (NAFLD) is affecting human populations that consume a western diet (Argyrou et al 2017)
We describe here the alterations in the gene expression profile and metabolite levels of HepaRG cells exposed to the polychlorinated biphenyl (PCB) congener 126, one of the most potent chemicals associated with development of toxicant-associated fatty liver disease (TAFLD) (Al-Eryani et al 2015)
It is recognized that occupational exposures to chemical pollutants can lead to NAFLD, there is limited information available regarding the mechanism by which typical environmental levels of exposure can contribute to the onset of this disease

Summary

Introduction

A growing epidemic of non-alcoholic fatty liver disease (NAFLD) is affecting human populations that consume a western diet (Argyrou et al 2017). The spectrum of NAFLD ranges from fatty infiltration of the liver (steatosis), to more advanced stages characterized by liver inflammation and fibrosis (non-alcoholic steatohepatitis, NASH), and subsequent cirrhosis, and hepatocellular carcinoma (Michelotti et al 2013; Vernon et al 2011). NAFLD currently affects 25% of the US population, and approximately 2–5% have NASH (Vernon et al 2011) with concomitant massive clinical and economic burden (Younossi et al 2016). Annual direct medical costs have been estimated to be approximately $103 billion ($1613 per patient) in the US. The occurrence of NAFLD in Europe is very high and ranges from 20 to 30% with annual medical costs. Some individuals develop NAFLD even if they do not have any of these risk factors (Foulds et al 2017) and with exposure to physiologically active environmental pollutants being a recognized additional determinant of disease establishment

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