Abstract：
Aryl hydrocarbon receptor (AHR) is one of the main mediators of the toxic effects of benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, a vast number of BaP- and TCDD-affected genes may suggest a more complex transcriptional regulatory network driving common adverse effects of these two chemicals. Unlike TCDD, BaP is rapidly metabolized in the liver, yielding products with a questionable ability to bind and activate AHR. In this study, we used transcriptomics data from the BaP- and TCCD-exposed human liver cell line HepG2, and performed differential eigengene network analysis to understand the correlation among genes and to untangle the common regulatory mechanism in the action of BaP and TCDD. The genes were grouped into 11 meta-modules with an overall preservation of 0.72 and were also segregated into three consensus time clusters: 12, 24, and 48 h. The analysis showed that the consensus genes in each time cluster were either directly regulated by the AHR or the AHR-TF interactions. Some TFs form a direct physical interaction with AHR such as ESR1, FOXA1, and E2F1, whereas others, including CTCF, RXRA, FOXO1, CEBPA, CEBPB, and TP53 show an indirect interaction with AHR. The analysis of biological processes (BPs) identified unique and common BPs in BaP and TCDD samples, with DNA damage response detected in all three time points. In summary, we identified a consensus transcriptional regulatory network common for BaP and TCDD consisting of direct AHR targets and AHR-TF targets. This analysis sheds new light on the common mechanism of action of a genotoxic (BaP) and non-genotoxic (TCDD) chemical in liver cells.
摘要：
芳香烃受体（AHR）是苯并[a]芘（BaP）和2,3,7,8-四氯二苯并对二恶英（TCDD）毒性作用的主要介质之一。然而,大量受BAP和TCDD影响的基因可能提示一个更复杂的转录调控网络,驱动这两种化学物质的共同不良反应.与TCDD不同,BaP在肝脏中快速代谢，产生具有可疑的结合和激活AHR能力的产品。在这项研究中,我们使用来自暴露于BAP和TCCD的人肝细胞系HepG2的转录组学数据，并进行差异特征基因网络分析，以了解基因之间的相关性，并阐明BaP和TCDD作用中的共同调节机制。将基因分为11个元模块，总体保留率为0.72，并分为三个共有时间簇：12、24和48h。分析表明，每个时间簇中的共有基因都直接受AHR或AHR-TF相互作用的调节。一些TFs与AHR形成直接的物理相互作用，如ESR1、FOXA1和E2F1，而另一些，包括CTCF，RXRA,FOXO1CEBPA,CEBPB,和TP53显示与AHR的间接相互作用。对生物过程（BPs）的分析确定了BaP和TCDD样品中独特和常见的BPs，在所有三个时间点检测到DNA损伤反应。总之,我们确定了BaP和TCDD共有的一致转录调控网络,由直接AHR靶标和AHR-TF靶标组成.该分析为肝细胞中基因毒性（BaP）和非基因毒性（TCDD）化学物质的共同作用机制提供了新的思路。
