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首页> 外文期刊>Biology of Reproduction: Offical Journal of the Society for the Study of Reproduction >Transcriptional suppression of Sertoli cell Timp2 in rodents following mono-(2-ethylhexyl) phthalate exposure is regulated by CEBPA and MYC.
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Transcriptional suppression of Sertoli cell Timp2 in rodents following mono-(2-ethylhexyl) phthalate exposure is regulated by CEBPA and MYC.

机译：塞尔托利氏细胞的转录抑制Timp2在啮齿动物mono - (2-ethylhexyl)邻苯二甲酸酯暴露受CEBPA MYC。

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摘要

Our previous studies showed that the prototypical testicular toxic phthalate monoester, mono-(2-ethylhexyl) phthalate (MEHP), suppresses Sertoli cell TIMP2 levels and allows for the activation of MMP2 in seminiferous epithelium. Activation of MMP2 is important for triggering germ cell apoptosis and instigating germ cell detachment from Sertoli cells. These novel findings led us to examine the transcriptional regulation of the Timp2 gene that accounts for the decrease in Sertoli cell TIMP2 levels following MEHP exposure. Sequential deletion of the Timp2 5'-upstream activating sequence (1200 bp) was used to survey transcriptional activation in the Timp2 promoter region in response to MEHP. Results indicate that under control conditions in rat Sertoli cells, CCAAT enhancer-binding protein alpha (CEBPA) acts as a transactivator to initiate Timp2 gene transcription, and its action is deactivated by exposure to MEHP. By contrast, MYC protein acts as an inhibitor of Timp2 gene transcription, and its activity is increased after MEHP treatment. Addition of follicle-stimulating hormone (FSH) to cells causes translocation of CEBPA into the Sertoli cell nucleus and rescues MEHP-suppressed TIMP2 levels. Down-regulation of TIMP2 expression by MEHP exposure is blocked by forskolin (a cAMP-elevating agent), suggesting that the decrease in Sertoli cell TIMP2 expression following MEHP exposure is cAMP-dependent. Taken together, these data indicate that MEHP both disrupts the FSH-stimulated cAMP signaling pathway and activates the inhibitory signaling mediated by MYC protein, to ultimately account for the cellular mechanism underlying the decreased expression of TIMP2 in Sertoli cells.
机译：我们以前的研究表明,典型的睾丸毒性邻苯二甲酸单酯,mono - (2-ethylhexyl)邻苯二甲酸二(MEHP),抑制塞尔托利氏细胞TIMP2水平和允许激活MMP2精上皮。对触发激活MMP2的重要生殖细胞凋亡和煽动生殖细胞从支持细胞分离。结果让我们检查转录Timp2基因占的监管塞尔托利氏细胞的减少TIMP2水平后MEHP曝光。Timp2 5的上游激活序列(1200bp)被用来调查转录激活在应对MEHP Timp2启动子区域。结果表明,在控制条件下大鼠足细胞,CCAAT enhancer-binding蛋白质α(CEBPA)充当反式激活因子启动Timp2基因转录,其行动由接触MEHP停用。MYC Timp2基因的蛋白质作为一种抑制剂转录,其活动增加MEHP治疗后。促卵泡激素(FSH)细胞导致易位CEBPA滋养细胞核和救助MEHP-suppressed TIMP2的水平。被forskolin (MEHP接触cAMP-elevating代理),这表明塞尔托利氏细胞减少TIMP2表达式cAMP-dependent MEHP曝光后。在一起,这些数据表明MEHP扰乱了FSH-stimulated阵营信号途径,激活抑制性信号由MYC蛋白质,最终账户细胞机制塞尔托利氏细胞表达TIMP2下降。

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