An eight-compound mixture but not corresponding concentrations of individual chemicals induces triglyceride accumulation in human liver cells. (July 2021)

• Record Type: Journal Article
• Authors: Lichtenstein, Dajana; Lasch, Alexandra; Alarcan, Jimmy; Mentz, Almut; Kalinowski, Jörn; Schmidt, Felix F.; Pötz, Oliver; Marx-Stoelting, Philip; Braeuning, Albert
• Is Part Of: Toxicology. Volume 459(2021)
• Publication Date: 2021-07
• Subjects: AMD amiodarone -- BA benzoic acid -- CA concentration addition -- CI combination index -- CYP cyproconazole -- DMSO dimethyl sulfoxide -- FLZ flusilazole -- GC-FID gas chromatography coupled to a flame ionization detector -- IA independent action -- IMZ imazalil -- LASSO least absolute shrinkage and selection operator -- MIE molecular initiating event -- NOAEL no-observed adverse effect level -- PCZ prochloraz -- PPC propiconazole -- PXR pregnane-X-receptor -- TBC tebuconazole; Hepatotoxicity -- Pregnane-X-receptor -- Steatosis -- Liver; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2021.152857
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: In real life, organisms are exposed to complex mixtures of chemicals at low concentration levels, whereas research on toxicological effects is mostly focused on single compounds at comparably high doses. Mixture effects deviating from the assumption of additivity, especially synergistic effects, are of concern. In an adverse outcome pathway (AOP)-guided manner, we analyzed the accumulation of triglycerides in human HepaRG liver cells by a mixture of eight steatotic chemicals (amiodarone, benzoic acid, cyproconazole, flusilazole, imazalil, prochloraz, propiconazole and tebuconazole), each present below its individual effect concentration at 1–3 μM. Pronounced and significantly enhanced triglyceride accumulation was observed with the mixture, and similar effects were seen at the level of pregnane-X-receptor activation, a molecular initiating event leading to hepatic steatosis. Transcript pattern analysis indicated subtle pro-steatotic changes at low compound concentrations, which did not exert measurable effects on cellular triglycerides. Mathematical modeling of mixture effects indicated potentially more than additive behavior using a model for compounds with similar modes of action. The present data underline the usefulness of AOP-guided in vitro testing for the identification of mixture effects and highlight the need for further research on chemical mixtures and harmonization of data interpretation of mixture effects.