Guo Junhai, Sartor Maureen, Karyala Saikumar, Medvedovic Mario, Kann Simone, Puga Alvaro, Ryan Patrick, Tomlinson Craig R
Division of Biostatistics and Epidemiology, University of Cincinnati, OH 45267-0056, USA.
Toxicol Appl Pharmacol. 2004 Jan 1;194(1):79-89. doi: 10.1016/j.taap.2003.09.002.
The molecular basis for the adverse biological effects of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD), a pervasive environmental toxin, is largely unknown. TCDD is a ligand for the cytosolic aromatic hydrocarbon receptor (AHR) which mediates the transcriptional induction of the xenobiotic metabolizing genes in the CYP1 family of cytochromes P450. Previous studies have suggested that the AHR may carry out important functions in the cell in addition to metabolizing toxins. We present gene expression profiles of smooth muscle cells from wild type and Ahr(-/-) mice that show significant changes in the RNA levels of the transforming growth factor-beta3 (Tgfb3) gene and genes involved in the modulation and processing of TGF-beta. The RNA expression profiles support a hypothesis that in the wild type, the AHR represses Tgfb gene expression and affects the gene expression of several TGF-beta-modulating and processing genes. We also observed that RNA levels increased for TGF-beta2, CYP1b1, and TGF-beta-related genes in Ahr(-/-) smooth muscle cells exposed to TCDD. These data are consistent with a hypothesis that TCDD stimulates the TGF-beta2 signaling pathway in the absence of the AHR to activate the Cyp1b1 gene. The above results provide a possible explanation for some of the multiple biological effects of TCDD and the physiological role played by the AHR in the absence of environmental agents.
二噁英（2,3,7,8-四氯二苯并对二噁英；TCDD）是一种普遍存在的环境毒素，其产生有害生物学效应的分子基础很大程度上尚不清楚。TCDD是胞质芳烃受体（AHR）的配体，该受体介导细胞色素P450的CYP1家族中异生物质代谢基因的转录诱导。先前的研究表明，AHR除了代谢毒素外，可能在细胞中发挥重要功能。我们展示了野生型和Ahr(-/-)小鼠平滑肌细胞的基因表达谱，这些谱显示转化生长因子-β3（Tgfb3）基因以及参与TGF-β调节和加工的基因的RNA水平有显著变化。RNA表达谱支持这样一种假说，即在野生型中，AHR抑制Tgfb基因表达并影响几个TGF-β调节和加工基因的表达。我们还观察到，在暴露于TCDD的Ahr(-/-)平滑肌细胞中，TGF-β2、CYP1b1和TGF-β相关基因的RNA水平升高。这些数据与一种假说一致，即TCDD在缺乏AHR的情况下刺激TGF-β2信号通路以激活Cyp1b1基因。上述结果为TCDD的多种生物学效应以及在没有环境因子时AHR所起的生理作用提供了一种可能的解释。
