Trichloroethylene perturbs HNF4a expression and activity in the developing chick heart

Alondra P. Harris, Kareem A. Ismail, Martha Nunez, Ira Martopullo, Alejandro Lencinas, Ornella Selmin, Raymond B Runyan

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Exposure to trichloroethylene (TCE) is linked to formation of congenital heart defects in humans and animals. Prior interactome analysis identified the transcription factor, Hepatocyte Nuclear Factor 4 alpha (HNF4a), as a potential target of TCE exposure. As a role for HNF4a is unknown in the heart, we examined developing avian hearts for HNF4a expression and for sensitivity to TCE and the HNF4a agonist, Benfluorex. In vitro analysis using a HNF4a reporter construct showed both TCE and HFN4a to be antagonists of HNF4a-mediated transcription at the concentrations tested. HNF4a mRNA is expressed transiently in the embryonic heart during valve formation and cardiac development. Embryos were examined for altered gene expression in the presence of TCE or Benfluorex. TCE altered expression of selected mRNAs including HNF4a, TRAF6 and CYP2C45. There was a transition between inhibition and induction of marker gene expression in embryos as TCE concentration increased. Benfluorex was largely inhibitory to selected markers. Echocardiography of exposed embryos showed reduced cardiac function with both TCE and Benfluorex. Cardiac contraction was reduced by 29% and 23%, respectively at 10 ppb. The effects of TCE and Benfluorex on autocrine regulation of HNF4a, selected markers and cardiac function argue for a functional interaction of TCE and HNF4a. Further, the dose-sensitive shift between inhibition and induction of marker expression may explain the nonmonotonic-like dose response observed with TCE exposure in the heart.

Original languageEnglish (US)
Pages (from-to)113-120
Number of pages8
JournalToxicology Letters
Volume285
DOIs
StatePublished - Mar 15 2018

Fingerprint

Hepatocyte Nuclear Factor 4
Trichloroethylene
benfluorex
Embryonic Structures
Gene expression
TNF Receptor-Associated Factor 6
Gene Expression
Echocardiography
Messenger RNA
Congenital Heart Defects
Heart Valves
Transcription

Keywords

  • Benfluorex
  • CYP2C45
  • CYP2H1
  • Heart defects
  • NFKBIE
  • Nonmonotonic dose response
  • TCE
  • TRAF6

ASJC Scopus subject areas

  • Toxicology

Cite this

Trichloroethylene perturbs HNF4a expression and activity in the developing chick heart. / Harris, Alondra P.; Ismail, Kareem A.; Nunez, Martha; Martopullo, Ira; Lencinas, Alejandro; Selmin, Ornella; Runyan, Raymond B.

In: Toxicology Letters, Vol. 285, 15.03.2018, p. 113-120.

Research output: Contribution to journalArticle

Harris, Alondra P. ; Ismail, Kareem A. ; Nunez, Martha ; Martopullo, Ira ; Lencinas, Alejandro ; Selmin, Ornella ; Runyan, Raymond B. / Trichloroethylene perturbs HNF4a expression and activity in the developing chick heart. In: Toxicology Letters. 2018 ; Vol. 285. pp. 113-120.
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AU - Ismail, Kareem A.

AU - Nunez, Martha

AU - Martopullo, Ira

AU - Lencinas, Alejandro

AU - Selmin, Ornella

AU - Runyan, Raymond B

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N2 - Exposure to trichloroethylene (TCE) is linked to formation of congenital heart defects in humans and animals. Prior interactome analysis identified the transcription factor, Hepatocyte Nuclear Factor 4 alpha (HNF4a), as a potential target of TCE exposure. As a role for HNF4a is unknown in the heart, we examined developing avian hearts for HNF4a expression and for sensitivity to TCE and the HNF4a agonist, Benfluorex. In vitro analysis using a HNF4a reporter construct showed both TCE and HFN4a to be antagonists of HNF4a-mediated transcription at the concentrations tested. HNF4a mRNA is expressed transiently in the embryonic heart during valve formation and cardiac development. Embryos were examined for altered gene expression in the presence of TCE or Benfluorex. TCE altered expression of selected mRNAs including HNF4a, TRAF6 and CYP2C45. There was a transition between inhibition and induction of marker gene expression in embryos as TCE concentration increased. Benfluorex was largely inhibitory to selected markers. Echocardiography of exposed embryos showed reduced cardiac function with both TCE and Benfluorex. Cardiac contraction was reduced by 29% and 23%, respectively at 10 ppb. The effects of TCE and Benfluorex on autocrine regulation of HNF4a, selected markers and cardiac function argue for a functional interaction of TCE and HNF4a. Further, the dose-sensitive shift between inhibition and induction of marker expression may explain the nonmonotonic-like dose response observed with TCE exposure in the heart.

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