Trichloroethylene perturbs HNF4a expression and activity in the developing chick heart

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.