Assessment of endocrine disruptor impacts on lipid metabolism in a fatty acid-supplemented HepaRG human hepatic cell line

• Published in: Chemosphere (Oxford) Vol. 349; p. 140883
• Main Authors: Bernal, Kévin, Touma, Charbel, Le-Grand, Béatrice, Rose, Sophie, Degerli, Selenay, Genêt, Valentine, Lagadic-Gossmann, Dominique, Coumoul, Xavier, Martin-Chouly, Corinne, Langouët, Sophie, Blanc, Etienne B
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2024; Elsevier
• Series: Chemosphere
• Subjects: Dichlorodiphenyl Dichloroethylene - metabolism; Diethylhexyl Phthalate - toxicity; Ecology, environment; Endocrine disruptors; Endocrine Disruptors - metabolism; Endocrinology and metabolism; Fatty Acids - metabolism; Fatty Liver - metabolism; Health; HepaRG; Hepatocytes; Human health and pathology; Humans; Life Sciences; Lipid Metabolism; MASLD; Mechanistic toxicology; Oleic Acid - metabolism; Oleic Acid - toxicity; Risk assessment; Toxicology; Endocrine disruptors; HepaRG; Lipid metabolism; MASLD; Risk assessment; Mechanistic toxicology
• ISSN: 0045-6535; 1879-1298
• DOI: 10.1016/j.chemosphere.2023.140883

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. This disease encompasses several stages, from steatosis to steatohepatitis and, eventually, to fibrosis and cirrhosis. Exposure to environmental contaminants is one of the risk factors and an increasing amount of evidence points to a role for endocrine disrupting compounds (EDCs). This study assesses the impact of selected EDCs on the formation of lipid droplets, the marker for steatosis in a hepatic model. The mechanisms underlying this effect are then explored. Ten compounds were selected according to their obesogenic properties: bisphenol A, F and S, butyl-paraben, cadmium chloride, p,p’-DDE, DBP, DEHP, PFOA and PFOS. Using a 2D or 3D model, HepaRG cells were exposed to the compounds with or without fatty acid supplementation. Then, the formation of lipid droplets was quantified by an automated fluorescence-based method. The expression of genes and proteins involved in lipid metabolism and the impact on cellular respiration was analyzed. The formation of lipid droplets, which is revealed or enhanced by oleic acid supplementation, was most effectively induced by p,p’-DDE and DEHP. Experiments employing either 2D or 3D culture conditions gave similar results. Both compounds induced the expression of PLIN2. p,p’-DDE also appears to act by decreasing in fatty acid oxidation. Some EDCs were able to induce the formation of lipid droplets, in HepaRG cells, an effect which was increased after supplementation of the cells with oleic acid. A full understanding of the mechanisms of these effects will require further investigation. The novel automated detection method described here may also be useful in the future as a regulatory test for EDC risk assessment. [Display omitted] •DEHP induces the formation of lipid droplets in human HepaRG cells.•Oleic acid (OA) supplementation enhances the steatotic effects of p,p’-DDE, DBP and DEHP.•Perilipin 2 is overexpressed after co-exposure to OA and EDCs.•p,p’-DDE exposure impairs long-chain fatty acid oxidation.•A method developed for lipid droplet quantification could be used as a regulatory test.