Di-N-Octylphthalate Acts as a Proliferative Agent in Murine Cell Hepatocytes by Regulating the Levels of TGF-β and pro-Apoptotic Proteins

Shelby Buckner, Allison Pruitt, Cecilia Thomas, Monisha Amin, Laurence L Miller, Faith E. Wiley, Maria Eugenia Sabbatini

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Abstract

Di-n-octylphthalate (DNOP) is a phthalate used in the manufacturing of a wide variety of polyvinyl chloride (PVC)-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. Healthy mouse hepatocyte AML-12 and FL83B cells were treated with DNOP (10, 100 and 1,000 ppm). The rate of cell proliferation was increased in treated cells with DNOP in a concentration-dependent manner as early as 24 h. Using quantitative PCR, DNOP caused an increase in expression of transforming growth factor-β (tgf-β) in both cell lines, and primary culture mouse hepatocytes. The novel selective TGF-β receptor type I/II (TβRI/II) inhibitor LY2109761 impaired the effect of DNOP on cell proliferation. The presence of pro-apoptotic proteins decreased in the presence of 1,000 ppm DNOP. In in-vitro and ex-vivo models, DNOP did not change the methylation status of any tumor suppressor gene studied. Our observation indicates that DNOP, through an increase in the expression of tgf-β and a decrease in the presence 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 for a month. Although DNOP had no effect on body weight or liver weight, it caused a decrease in albumin and increase in vimentin indicating an epithelial-to-mesenchymal transition state in mouse hepatocytes. Mice exposed to DNOP displayed cholestasis, which was reflected in an increase in hepatic bile acids and glutathione levels.
Original languageEnglish (US)
Pages (from-to)166-175
JournalFood and Chemical Toxicology
Volume111
StatePublished - Jan 2018

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Apoptosis Regulatory Proteins
hepatocytes
Hepatocytes
mice
Cell proliferation
Transforming Growth Factors
liver
Liver
transforming growth factors
Cells
cells
lesions (animal)
Methylation
Consumer products
cell proliferation
Vimentin
Bile Acids and Salts
Polyvinyl Chloride
Cell culture
Cell Proliferation

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Di-N-Octylphthalate Acts as a Proliferative Agent in Murine Cell Hepatocytes by Regulating the Levels of TGF-β and pro-Apoptotic Proteins. / Buckner, Shelby; Pruitt, Allison; Thomas, Cecilia; Amin, Monisha; Miller, Laurence L; Wiley, Faith E.; Sabbatini, Maria Eugenia.

In: Food and Chemical Toxicology, Vol. 111, 01.2018, p. 166-175.

Research output: Contribution to journalArticle

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abstract = "Di-n-octylphthalate (DNOP) is a phthalate used in the manufacturing of a wide variety of polyvinyl chloride (PVC)-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. Healthy mouse hepatocyte AML-12 and FL83B cells were treated with DNOP (10, 100 and 1,000 ppm). The rate of cell proliferation was increased in treated cells with DNOP in a concentration-dependent manner as early as 24 h. Using quantitative PCR, DNOP caused an increase in expression of transforming growth factor-β (tgf-β) in both cell lines, and primary culture mouse hepatocytes. The novel selective TGF-β receptor type I/II (TβRI/II) inhibitor LY2109761 impaired the effect of DNOP on cell proliferation. The presence of pro-apoptotic proteins decreased in the presence of 1,000 ppm DNOP. In in-vitro and ex-vivo models, DNOP did not change the methylation status of any tumor suppressor gene studied. Our observation indicates that DNOP, through an increase in the expression of tgf-β and a decrease in the presence 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 for a month. Although DNOP had no effect on body weight or liver weight, it caused a decrease in albumin and increase in vimentin indicating an epithelial-to-mesenchymal transition state in mouse hepatocytes. Mice exposed to DNOP displayed cholestasis, which was reflected in an increase in hepatic bile acids and glutathione levels.",
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