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Trichloroethylene Produced Defects in the Developing Heart Involve the Transcription Factor, HNF4a
Author(s) -
Chen Sheri,
Nunez Martha,
Ismail Kareem,
Selmin Ornella,
Runyan Raymond Bruce
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.555.4
Subject(s) - trichloroethylene , hepatocyte nuclear factors , transcription factor , chemistry , gene expression , western blot , hepatocyte nuclear factor 4 , gene , gata4 , endocrinology , medicine , microbiology and biotechnology , biology , nuclear receptor , biochemistry , environmental chemistry
Trichloroethylene, TCE, is an organic solvent known to cause congenital heart disease in animals. Prior studies showed that TCE alters calcium homeostasis and myocyte contraction and transcription of more than 4000 genes. Bioinformatic analysis of altered gene transcription suggested that Hepatocyte nuclear factor 4, alpha (HNF4α) may be a central target for TCE. HNF4a was linked to 75% of the nodes in a TCE interactome. HNF4α is transcription factor that plays a significant role in developing liver, kidney, and intestines. Though not previously reported, it can be found in the embryonic heart by PCR and western blot. To explore the connection between TCE and HNF4a, we exposed pregnant mice to TCE (11μM) or the HNF4a agonists/anatagonists Bi6015 and Benfluorex (10 μM) in maternal drinking water. Embryos were collected on day 10.5 and hearts were dissected and pooled for each litter. RNA was isolated and synthesized into cDNA for quantitative PCR analysis of marker gene expression. Fourteen markers were selected from previous microarray studies in mouse or chick embryo models as being significantly altered by TCE exposure during development. TCE inhibited expression of each the selected marker genes while Benfluorex and Bi6015 were agonists of their expression. The overlap between HNF4a and TCE regulation of the selected markers was complete. Bi6015 activity varied as an agonist or antagonist in culture depending on concentration. The data support the hypothesis that HNF4a is a direct target of TCE exposure during heart development. Further studies will explore the direct binding of TCE and Benfluorex to HNF4a. Support or Funding Information NIEHS P30 ES006694