Di (2-Ethylhexyl) Phthalate and Its Role in Developing Cholestasis: An In Vitro Study on Different Liver Cell Types

ABSTRACTObjectives:Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in many polyvinylchloride medical devices and is washed out easily. Thereby critically ill infants can become exposed to DEHP concentrations significantly exceeding the recommended threshold. We suspect DEHP to play an important role in the development of intestinal failure-associated liver disease. The aim of this study was therefore to determine the direct influence of DEHP on different liver cell types.Methods:HepG2, human upcyte hepatocytes, primary murine hepatocytes, LX-2, human upcyte hepatic stellate cells, and liver organoids were cultured with DEHP (0.5–500 μmol/L) and parameters including cytotoxicity, cell–cell interactions, and expression of metabolizing enzymes were investigated.Results:DEHP modulated the expression of xenobiotic metabolizing enzymes, reduced the formation of bile canaliculi and cell polarity, and inhibited Cyp-activity in hepatocytes. DEHP had a toxic effect on LX-2 and induced the fibrogenic activation of hepatic stellate cells. The mode of action of DEHP was different in monolayer cultures compared to 3D-liver organoids, which were more sensitive to DEHP.Conclusions:This study suggests that DEHP modulates expression and activity of drug-detoxifying liver enzymes in humans at a clinically relevant concentration. Furthermore, it may contribute to the development of cholestasis and fibrosis. These findings strongly support the opinion, that there is a significant potential for serious adverse effects of DEHP derived from medical devices on human health, especially in very young infants with immature livers. Objectives: Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in many polyvinylchloride medical devices and is washed out easily. Thereby critically ill infants can become exposed to DEHP concentrations significantly exceeding the recommended threshold. We suspect DEHP to play an important role in the development of intestinal failure-associated liver disease. The aim of this study was therefore to determine the direct influence of DEHP on different liver cell types. Methods: HepG2, human upcyte hepatocytes, primary murine hepatocytes, LX-2, human upcyte hepatic stellate cells, and liver organoids were cultured with DEHP (0.5–500 μmol/L) and parameters including cytotoxicity, cell–cell interactions, and expression of metabolizing enzymes were investigated. Results: DEHP modulated the expression of xenobiotic metabolizing enzymes, reduced the formation of bile canaliculi and cell polarity, and inhibited Cyp-activity in hepatocytes. DEHP had a toxic effect on LX-2 and induced the fibrogenic activation of hepatic stellate cells. The mode of action of DEHP was different in monolayer cultures compared to 3D-liver organoids, which were more sensitive to DEHP. Conclusions: This study suggests that DEHP modulates expression and activity of drug-detoxifying liver enzymes in humans at a clinically relevant concentration. Furthermore, it may contribute to the development of cholestasis and fibrosis. These findings strongly support the opinion, that there is a significant potential for serious adverse effects of DEHP derived from medical devices on human health, especially in very young infants with immature livers.

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