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

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.

[What do we know about effects of the endocrine disruptors on metabolism and obesity?] / Que sait-on de l'action des perturbateurs endocriniens sur le métabolisme et l'obésité?

WHAT DO WE KNOW ABOUT EFFECTS OF THE ENDOCRINE DISRUPTORS ON METABOLISM AND OBESITY? Some endocrine disruptors (EDs) are suspected to be involved in the increase of the prevalence of obesity and metabolic diseases. Data from epidemiological, in vivo, in vitro and in silico studies suggest that EDs may exert their effects on numerous tissues involved in energy metabolism and in the regulation of appetite: adipose tissue, liver, muscle, pancreas, gut and hypothalamus. Their effects are due to: disruptions of the carbohydrate and lipid homeostasis in these organs, via the activation of specific nuclear receptors or transcriptional factors, disturbances in communication between these organs, and epigenetic mechanisms, involved for example in intergenerational effects. The characterization of the effects of EDs on endocrine systems is still under investigations in several European and international projects and initiatives, with the aim to establish new validated regulatory tests for ED identification.

QUE SAIT-ON DE L'ACTION DES PERTURBATEURS ENDOCRINIENS SUR LE MÉTABOLISME ET L'OBÉSITÉ ? Certains perturbateurs endocriniens (PE) semblent être impliqués dans l'augmentation de la prévalence de l'obésité et des maladies métaboliques. Les données provenant d'études épidémiologiques, in vivo, in vitro et in silico suggèrent que les PE exerceraient leurs effets sur de nombreux tissus impliqués dans le métabolisme énergétique ou la régulation de l'appétit : tissu adipeux, foie, muscle, pancréas, intestin et hypothalamus. Les effets sont liés : aux perturbations de l'homéostasie glucido-lipidique dans ces organes, via l'activation de récepteurs nucléaires ou facteurs transcriptionnels spécifiques ; aux perturbations de la communication entre ces organes et aux mécanismes épigénétiques, impliqués par exemple dans les effets intergénérationnels. La caractérisation des effets des PE sur les systèmes endocriniens se poursuit, au sein d'initiatives et de projets européens et internationaux qui, à terme, mèneront à la mise en place de tests réglementaires validés pour l'identification des perturbateurs endocriniens.