Role of aryl hydrocarbon receptor in the antiandrogenic activities of polycyclic aromatic hydrocarbons

在雄激素应答细胞系中研究了芳烃受体（AhR）在多环芳烃（PAHs）抗雄激素活性中的作用。所得结果如下：1. 多环芳烃代谢物的抗雄激素活性较弱，因此多环芳烃代谢物的贡献不显著。2. 抗雄激素多环芳烃不降低细胞雄激素浓度，也不降低雄激素受体（AR）表达水平。3. 抗雄激素多环芳烃诱导AR-AhR蛋白复合物的形成。4. 虽然DJ-1是一种与AR形成复合物的蛋白质，并参与雄激素作用的控制，但DJ-1与AR之间的复合物形成不受抗雄激素PAHs处理的影响。5. 虽然在雄激素调控基因的启动子/增强子区域存在外源应答元件（ahr结合序列），但外源应答元件并不重要。这些结果表明，被PAH激活的AhR与AR形成复合物，从而抑制AR作为转录因子的功能，导致PAHs具有抗雄激素活性。接下来，我们在雄激素应答细胞系中研究了AhR和AR之间的串扰。所得结果如下：6. 雄激素5α-二氢睾酮（DHT）上调ahr调控基因CYP1A1基因mRNA水平，且该作用呈浓度依赖性。7. R1881是一种具有激动剂活性的合成雄激素，具有类似的活性。8. DHT在细胞中没有显示出AR被siRNA敲除的效果。DHT在报告基因表达仅依赖于AR反应元件的报告系统中没有活性。这些结果表明，在AhR和AR信号转导通路之间存在着串扰。

Role of aryl hydrocarbon receptor (AhR) in the antiandrogenic activities of polycyclic aromatic hydrocarbons (PAHs) was studies in androgen responsive cell lines. Results obtained are as follows. 1. Antiandrogenic activities of metabolites of PAHs were weak, and therefore, the contribution of metabolites of PAHs is not significant. 2. Decrease in neither cellular androgen concentration nor androgen receptor (AR) expression level was caused by treatment with the antiandrogenic PAHs. 3. Formation of AR-AhR protein complex was induced by treatment with the antiandrogenic PAHs. 4. While DJ-1 is a protein that form a complex with AR and is involved in the control of androgenic action, the complex formation between DJ-1 and AR was not affected by treatment with the antiandrogenic PAHs. 5. While xenobiotic responsive element (AhR-binding sequence) exists in the promoter/enhancer regions of androgen-regulated genes, xenobiotic response element is not important. These results demonstrate that AhR activated by PAH forms a complex with AR and consequently inhibits the function of AR as a transcription factor, leading to the antiandrogenic activities of PAHs. Next, the cross-talk between AhR and AR was studied in androgen responsive cell lines. The results obtained are as follows. 6. 5α-Dihydrotestosterone (DHT), an androgen, elevated the mRNA level of CYP1A1 gene, an AhR-regulated gene and this effect was concentration-dependent. 7. R1881, a synthetic androgen with agonist activity, has a similar activity. 8. DHT does not show the effect in the cell that AR is knocked-down by siRNA for AR. 9. DHT shows no activity in the reporter assay system in which expression of reporter gene is dependent upon only AR responsive element. These results indicate that there exists the cross-talk between AhR and AR signal transduction pathways.