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Issue 3, 2020
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HNF4a transcription is a target of trichloroethylene toxicity in the embryonic mouse heart

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Abstract

In exploration of congenital heart defects produced by TCE, Hepatocyte Nuclear Factor 4 alpha (HNF4a) transcriptional activity was identified as a central component. TCE exposure altered gene transcription in the chick heart in a non-monotonic pattern where only low dose exposure inhibited transcription by HNF4a. As the chick embryo is non-placental, we examine here HNF4a as a target of TCE in developing mouse embryos. Benfluorex and Bi6015, published agonist and antagonist, respectively, of HNF4a were compared to low dose TCE exposure. Pregnant mice were exposed to 10 ppb (76 nM) TCE, 5 μM Benfluorex, 5 μM Bi6015, or a combination of Bi6015 and TCE in drinking water. Litters (E12) were collected during a sensitive window in heart development. Embryonic hearts were collected, pooled for extraction of RNA and marker expression was examined by quantitative PCR. Multiple markers, previously identified as sensitive to TCE exposure in chicks or as published targets of HNF4a transcription were significantly affected by Benfluorex, Bi6015 and TCE. Activity of TCE and both HNF4a-specific reagents on transcription argues that HNF4a is a component of TCE cardiotoxicity and likely a proximal target of low dose exposure during development. The effectiveness of these reagents after delivery in maternal drinking water suggests that neither maternal metabolism, nor placental transport is protective of exposure.

Graphical abstract: HNF4a transcription is a target of trichloroethylene toxicity in the embryonic mouse heart

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Article information


Submitted
20 Dec 2019
Accepted
26 Feb 2020
First published
05 Mar 2020

Environ. Sci.: Processes Impacts, 2020,22, 824-832
Article type
Paper

HNF4a transcription is a target of trichloroethylene toxicity in the embryonic mouse heart

S. Chen, A. Lencinas, M. Nunez, O. I. Selmin and R. B. Runyan, Environ. Sci.: Processes Impacts, 2020, 22, 824
DOI: 10.1039/C9EM00597H

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