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.

中文翻译：

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HNF4a转录是胚胎小鼠心脏中三氯乙烯毒性的靶标。

在探索由TCE产生的先天性心脏缺陷中，肝细胞核因子4α（HNF4a）转录活性被确定为主要成分。TCE暴露以非单调的方式改变了雏鸡心脏中的基因转录，其中仅低剂量暴露会抑制HNF4a的转录。由于鸡胚是非胎盘的，因此我们在这里检查HNF4a作为TCE在发育中的小鼠胚胎中的靶标。将分别发表的HNF4a激动剂和拮抗剂Benfluorex和Bi6015与低剂量TCE暴露进行了比较。怀孕的小鼠在饮用水中暴露于10 ppb（76 nM）TCE，5μMBenfluorex，5μMBi6015或Bi6015和TCE的组合。在心脏发育的敏感期收集垃圾（E12）。收集了胚胎的心脏，收集RNA提取物，并通过定量PCR检查标志物表达。Benfluorex，Bi6015和TCE显着影响了多种标记，这些标记先前被鉴定为对小鸡的TCE暴露敏感或已发布的HNF4a转录靶标。TCE和两种HNF4a特异性试剂在转录上的活性都认为HNF4a是TCE心脏毒性的成分，并且很可能是发育过程中低剂量暴露的近端靶标。这些试剂在母体饮用水中分娩后的有效性表明，母体代谢和胎盘运输均不能保护其暴露。TCE和两种HNF4a特异性试剂在转录上的活性都认为HNF4a是TCE心脏毒性的组成部分，可能是发育过程中低剂量暴露的近端靶标。这些试剂在母体饮用水中分娩后的有效性表明，母体代谢和胎盘运输均不能保护其暴露。TCE和两种HNF4a特异性试剂在转录上的活性都认为HNF4a是TCE心脏毒性的成分，并且很可能是发育过程中低剂量暴露的近端靶标。这些试剂在母体饮用水中分娩后的有效性表明，母体代谢和胎盘运输均不能保护其暴露。