Differential Action of Chlorinated Polycyclic Aromatic Hydrocarbons on Aryl Hydrocarbon Receptor-Mediated Signaling in Breast Cancer Cells
Differential Action of Chlorinated Polycyclic Aromatic Hydrocarbons on Aryl Hydrocarbon Receptor-Mediated Signaling in Breast Cancer Cells
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DOI：
10.1002/tox.20488
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发表时间：
2010-04-01
影响因子：
4.5
通讯作者：
Shimoi, Kayoko
中科院分区：
文献类型：
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作者：
Ohura, Takeshi;Morita, Maki;Shimoi, Kayoko
氯化多环芳烃（CIPAHs）是一系列卤化芳烃，已在环境中被发现。其代谢激活的第一步似乎与芳烃受体（AhR）介导的细胞色素P450 (CYP) 1家族的诱导有关，尽管证据尚不清楚。在本研究中，我们首先研究了5种具有3 - 5环的CIPAHs及其亲本PAHs对人乳腺癌MCF-7细胞中CYP1A1和1131表达的影响。对于靶向的多环芳烃，Western blot分析显示，与对应亲本多环芳烃相比，cipah诱导的CYP1A1和1131的活性增强，其中氯化作用对菲的影响尤为突出。在进一步的研究中，使用6-氯苯并[a]芘（6-CIBaP）与17 β -雌二醇共处理显示CYP1B1 mRNA表达增加，但CYP1A1 mRNA表达未增加。由于已有报道称AhR配体可诱导AhR-雌激素受体（ER）复合物的形成，从而刺激ER靶基因的转录，因此本研究也探讨了CIPAHs在转染了雌激素反应元件调控的绿色荧光蛋白（GFP）报告基因的MCF-7细胞中的作用。6-CIBaP通过激活AhR诱导细胞中与ER信号相关的GFP表达呈剂量依赖性增加，而3,9,10-三氯菲（3,9,10- cl (3)CIPhe）尽管具有激活AhR的能力，但却没有。此外，我们还研究了CIPAHs对MCF-7细胞内源性er反应基因组织蛋白酶D表达的影响。6-CIBaP刺激er反应基因的表达，而3,9,10- cl (3)CIPhe没有，与GFP表达系统一样。这些结果表明，雌激素作用介导的内质网信号通过AhR激活不一定发生在每一个可以激活AhR的配体。(C) 2009 Wiley期刊公司环境科学与技术，2009,31(2):1 - 7。
Chlorinated polycyclic aromatic hydrocarbons (CIPAHs), which are a series of halogenated aromatic hydrocarbons, have been found in the environment. The primary step in their metabolic activation seems to be associated with aryl hydrocarbon receptor (AhR)-mediated induction of the cytochrome P450 (CYP) 1 family, although the evidence remains unclear. In this study, we first investigated the effects of five CIPAHs with three to five rings and the corresponding parent PAHs on the expression of CYP1A1 and 1131 in human breast cancer MCF-7 cells. For the targeted CIPAHs, Western blot analysis of CIPAH-induced CYP1A1 and 1131 showed an enhancement in activities in comparison with induction by the corresponding parent PAHs, and the effects of chlorination were especially prominent in phenanthrene. In a further study, using 6-chlorobenzo[a]pyrene (6-CIBaP), cotreatment with 17 beta-estradiol showed an increase in the expression of CYP1B1 mRNA but not CYP1A1 mRNA. Since the AhR ligand has been reported to induce formation of an AhR-estrogen receptor (ER) complex, which stimulates transcription of ER target genes, the effects of CIPAHs in MCF-7 cells transfected with estrogen response elements-regulated green fluorescent protein (GFP) reporter genes were also investigated in this study. 6-CIBaP induced a dose-dependent increase in GFP expression related to ER signaling through AhR activation in the cells, but 3,9,10-trichlorophenanthrene (3,9,10-Cl(3)CIPhe) did not, despite its ability to activate AhR. Furthermore, we investigated the effect of CIPAHs on the expression of the endogenous ER-responsive genes, cathepsin D, in MCF-7 cells. 6-CIBaP stimulated expression of the ER-responsive genes but 3,9,10-Cl(3)CIPhe did not, as in the GFP expression system. These results suggest that estrogenic action mediated ER signaling through AhR activation does not necessarily occur for every ligand that can activate AhR. (C) 2009 Wiley Periodicals, Inc. Environ Toxicol 25: 180-187, 2010.