Di-N-octylphthalate acts as a proliferative agent in murine cell hepatocytes by regulating the levels of TGF-β and pro-apoptotic proteins

• Published in: Food and chemical toxicology Vol. 111; pp. 166 - 175
• Main Authors: Buckner, Shelby L., Pruitt, Allison N., Thomas, Cecilia N., Amin, Monisha Y., Miller, Laurence L., Wiley, Faith E., Sabbatini, Maria Eugenia
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2018
• Subjects: Apoptosis; Cholestasis; Di-n-octylphthalate; Hepatocyte; Mitosis; Transforming growth factor-β; Hepatocyte; Di-n-octylphthalate; Mitosis; Transforming growth factor-β; Cholestasis; Apoptosis
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2017.11.005

Di-n-octylphthalate (DNOP) is a phthalate used in the manufacturing of a wide variety of polyvinyl chloride-containing medical and consumer products. A study on chronic exposure to DNOP in rodents showed the development of pre-neoplastic hepatic lesions following exposure to a tumor initiator. The objective of this study was to identify the mechanisms by which DNOP leads to pre-neoplastic hepatic lesions. Mouse hepatocyte AML-12 and FL83B cells were treated with DNOP. The rate of cell proliferation was increased in treated cells in a concentration-dependent manner. DNOP increased the expression of transforming growth factor-β (tgf-β) in both cell lines, and primary culture mouse hepatocytes. The TGF-β receptor inhibitor LY2109761 impaired the effect of DNOP. The presence of pro-apoptotic proteins decreased in the presence of DNOP. Our observation indicates that DNOP, through an increase in the expression of tgf-β and a decrease in the levels of pro-apoptotic proteins, acts as a proliferative agent in normal mouse hepatocytes. We also studied the morphological and functional changes of the mouse liver upon a short-term treatment of DNOP. Mice exposed to DNOP displayed an epithelial-to-mesenchymal transition and cholestasis, which was reflected in an increase in hepatic bile acids and glutathione levels. Graphical abstract of the mechanism by which DNOP causes pre-neoplastic lesions. The figure shows that DNOP causes an increase in the rate of cell proliferation of normal hepatocytes through an increase in the expression of tgf-β and a decrease in pro-apoptotic proteins, while initiating an EMT state likely through an increase in tgf-β. Both the increase in cell proliferation and an induction of EMT arise in pre-neoplastic lesions. [Display omitted] •DNOP increased cell proliferation through an up-regulation of tgf-β.•A down-regulation of pro-apoptotic proteins can be part of the mitogenic effect.•DNOP caused an epithelial-to-mesenchymal transition, likely via increased tgf-β levels.•Short-term consumption of DNOP caused cholestasis in mice.•Short-term consumption of DNOP increased hepatic bile acid and glutathione levels.