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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

Scholary Output:
Contribution to journal
Article
 Peer-review

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.

Publication Information

Output type

Scholary Output:
Contribution to journal
Article
 Peer-review

Original language

English (US)

Pages from-to (Number of pages)

Pages 166-175

Journal (Volume, Issue Number)

Food and Chemical Toxicology (Volume 111)

Publication milestones

  • Published - 01/2018

Publication status

Published - 01/2018

ISSN

0278-6915

Publication IDs

  • Scopus: 85039936151
  • ORCID: /0000-0001-7100-2482/work/51190917
  • PubMed: 29128616
  • ORCID: /0000-0002-0916-2685/work/67746054

Publication metrics

Metrics

Fractional count
3
Fractional count
0.43
Fractional count
4
Fractional count
0.57
Fractional count
3
Fractional count
1
SciVal
FWCI
0.22
SciVal
Author count
7
SciVal
citations
2
SciVal
Paper percentile
49
Scopus
citations
5, opens in new tab

PlumX

Captures
8
Citation count
3