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Trichloroethylene perturbs HNF4a expression and activity in the developing chick heart

Alondra P Harris1, Kareem A Ismail1, Martha Nunez1

  • 1Department of Cellular & Molecular Medicine, University of Arizona, Tucson, AZ 85724-5044, United States.

Toxicology Letters
|January 7, 2018
PubMed

Insights

Trichloroethylene (TCE) exposure impacts heart development by interfering with Hepatocyte Nuclear Factor 4 alpha (HNF4a). This study reveals TCE and an HNF4a agonist reduce cardiac function and alter gene expression in developing hearts.

Area of Science:

  • Environmental Toxicology
  • Developmental Biology
  • Cardiovascular Research

Background:

  • Trichloroethylene (TCE) exposure is associated with congenital heart defects.
  • Hepatocyte Nuclear Factor 4 alpha (HNF4a) was identified as a potential TCE target.
  • The role of HNF4a in cardiac development was previously unknown.

Purpose of the Study:

  • To investigate the expression of HNF4a in developing avian hearts.
  • To determine the sensitivity of developing hearts to TCE and an HNF4a agonist, Benfluorex.
  • To explore the functional interaction between TCE and HNF4a in cardiac development.

Main Methods:

  • In vitro analysis using HNF4a reporter constructs to assess transcriptional activity.
  • Quantitative analysis of HNF4a mRNA expression during embryonic heart development.
  • Gene expression profiling of cardiac tissues exposed to TCE and Benfluorex.
  • Echocardiography to evaluate cardiac function in exposed embryos.

Main Results:

  • TCE and Benfluorex antagonized HNF4a-mediated transcription in vitro.
  • HNF4a mRNA was transiently expressed during critical stages of heart development.
  • TCE exposure altered the expression of key genes, including HNF4a, TRAF6, and CYP2C45, with a dose-dependent shift from inhibition to induction.
  • Benfluorex primarily inhibited selected marker gene expression.
  • Both TCE and Benfluorex significantly reduced cardiac function, with decreased contraction observed at 10 ppb.

Conclusions:

  • The findings support a functional interaction between TCE and HNF4a in cardiac development.
  • The observed dose-sensitive shift in gene expression may explain non-monotonic dose-response patterns in TCE-induced heart defects.
  • TCE and Benfluorex impair cardiac function, highlighting the vulnerability of the developing heart to environmental exposures and HNF4a pathway disruption.
Keywords:
BenfluorexCYP2C45CYP2H1Heart defectsNFKBIENonmonotonic dose responseTCETRAF6

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