Fan WuQiang, Yanase Toshihiko, Morinaga Hidetaka, Gondo Shigeki, Okabe Taijiro, Nomura Masatoshi, Komatsu Tomoko, Morohashi Ken-Ichirou, Hayes Tyrone B, Takayanagi Ryoichi, Nawata Hajime
Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Environ Health Perspect. 2007 May;115(5):720-7. doi: 10.1289/ehp.9758. Epub 2007 Feb 5.
Atrazine is a potent endocrine disruptor that increases aromatase expression in some human cancer cell lines. The mechanism involves the inhibition of phosphodiesterase and subsequent elevation of cAMP.
We compared steroidogenic factor 1 (SF-1) expression in atrazine responsive and non-responsive cell lines and transfected SF-1 into nonresponsive cell lines to assess SF-1's role in atrazine-induced aromatase. We used a luciferase reporter driven by the SF-1-dependent aromatase promoter (ArPII) to examine activation of this promoter by atrazine and the related simazine. We mutated the SF-1 binding site to confirm the role of SF-1. We also examined effects of 55 other chemicals. Finally, we examined the ability of atrazine and simazine to bind to SF-1 and enhance SF-1 binding to ArPII.
Atrazine-responsive adrenal carcinoma cells (H295R) expressed 54 times more SF-1 than nonresponsive ovarian granulosa KGN cells. Exogenous SF-1 conveyed atrazine-responsiveness to otherwise nonresponsive KGN and NIH/3T3 cells. Atrazine induced binding of SF-1 to chromatin and mutation of the SF-1 binding site in ArPII eliminated SF-1 binding and atrazine-responsiveness in H295R cells. Out of 55 chemicals examined, only atrazine, simazine, and benzopyrene induced luciferase via ArPII. Atrazine bound directly to SF-1, showing that atrazine is a ligand for this "orphan" receptor.
The current findings are consistent with atrazine's endocrine-disrupting effects in fish, amphibians, and reptiles; the induction of mammary and prostate cancer in laboratory rodents; and correlations between atrazine and similar reproductive cancers in humans. This study highlights the importance of atrazine as a risk factor in endocrine disruption in wildlife and reproductive cancers in laboratory rodents and humans.
阿特拉津是一种强效内分泌干扰物，可增加某些人类癌细胞系中芳香化酶的表达。其机制涉及磷酸二酯酶的抑制及随后环磷酸腺苷（cAMP）的升高。
我们比较了阿特拉津反应性和非反应性细胞系中类固醇生成因子1（SF-1）的表达，并将SF-1转染到非反应性细胞系中，以评估SF-1在阿特拉津诱导的芳香化酶中的作用。我们使用由SF-1依赖性芳香化酶启动子（ArPII）驱动的荧光素酶报告基因来检测阿特拉津和相关的西玛津对该启动子的激活作用。我们对SF-1结合位点进行突变以确认SF-1的作用。我们还检测了其他55种化学物质的影响。最后，我们检测了阿特拉津和西玛津与SF-1结合以及增强SF-1与ArPII结合的能力。
阿特拉津反应性肾上腺癌细胞（H295R）中SF-1的表达比非反应性卵巢颗粒细胞KGN高54倍。外源性SF-1赋予了原本无反应性的KGN和NIH/3T3细胞阿特拉津反应性。阿特拉津诱导SF-与染色质结合，ArPII中SF-1结合位点的突变消除了H295R细胞中的SF-1结合及阿特拉津反应性。在所检测的55种化学物质中，只有阿特拉津、西玛津和苯并芘通过ArPII诱导荧光素酶。阿特拉津直接与SF-1结合，表明阿特拉津是这种“孤儿”受体的配体。
目前的研究结果与阿特拉津在鱼类、两栖动物和爬行动物中的内分泌干扰作用、在实验啮齿动物中诱发乳腺癌和前列腺癌以及在人类中阿特拉津与类似生殖系统癌症之间的相关性相一致。本研究强调了阿特拉津作为野生动物内分泌干扰和实验啮齿动物及人类生殖系统癌症风险因素的重要性。
