Assessment of endocrine disruptor impact on carbohydrate metabolism in the HepaRG human hepatic cell line

Endocrine-disrupting chemicals (EDCs) are increasingly implicated in the development of metabolic disorders such as type 2 diabetes mellitus (T2DM). As hepatic dysfunction is a hallmark of early metabolic disease, we investigated how EDCs may contribute to glucose dysregulation using human HepaRG cells. Ten EDCs-bisphenol A (BPA), bisphenol F (BPF), bisphenol S (BPS), cadmium chloride (CdCl₂, 1 µM), butylparaben (BP), 1,1-dichloro-2,2-bis(4-chlorophenyl)ethene (p,p'-DDE), dibutyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP), perfluorooctanoic acid (PFOA), and perfluorooctanesulfonic acid (PFOS)-were tested at 25 µM for 5 days. We assessed multiple endpoints related to carbohydrate metabolism, including gene expression, mitochondrial function, glycogen content, glucose export, glycolytic capacity, and lactate release. Among the tested compounds, p,p'-DDE induced the most pronounced metabolic disruption, significantly reducing glycogen storage, glycolytic capacity, lactate export, and the expression of key genes involved in glucose metabolism. Using luciferase-based reporter cell lines, p,p'-DDE was found to activate primarily the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR). However, siRNA-mediated knockdown of these receptors did not reverse the changes induced by p,p'-DDE in gene expression, suggesting a more complex or alternative mechanism of action. These findings demonstrate that p,p'-DDE perturbs hepatic carbohydrate metabolism and may contribute to the pathogenesis of T2DM, highlighting the need for further mechanistic investigation.