Science Park Research Division, Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
Mol Cancer Res. 2012 Apr;10(4):546-57. doi: 10.1158/1541-7786.MCR-11-0605.
Environmental exposures during sensitive windows of development can reprogram normal physiologic responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyperresponsiveness to hormone in the adult uterus and promotion of hormone-dependent uterine leiomyoma. We show here that the environmental estrogens genistein, a soy phytoestrogen, and the plasticizer bisphenol A, differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. Whereas both genistein and bisphenol A induce genomic estrogen receptor (ER) signaling in the developing uterus, only genistein induced phosphoinositide 3-kinase (PI3K)/AKT nongenomic ER signaling to the histone methyltransferase enhancer of zeste homolog 2 (EZH2). As a result, this pregenomic signaling phosphorylates and represses EZH2 and reduces levels of H3K27me3 repressive mark in chromatin. Furthermore, only genistein caused estrogen-responsive genes in the adult myometrium to become hyperresponsive to hormone; estrogen-responsive genes were repressed in bisphenol A-exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by genistein promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, whereas bisphenol A did not. These data show that environmental estrogens have distinct nongenomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis.
环境暴露在发育的敏感窗口中可以重新编程正常的生理反应,并在发育重编程过程中改变生命后期的疾病易感性。例如,在生殖道发育过程中暴露于外源性雌激素己烯雌酚会重新编程子宫肌层中雌激素反应基因的表达,导致成年子宫对激素的超反应性,并促进激素依赖性子宫平滑肌瘤的发生。我们在这里表明,环境雌激素染料木黄酮(一种大豆植物雌激素)和增塑剂双酚 A 在其发育重编程模式和促进子宫肿瘤发生(平滑肌瘤)方面存在差异。尽管染料木黄酮和双酚 A 均能诱导发育中子宫的基因组雌激素受体(ER)信号,但只有染料木黄酮能诱导磷酸肌醇 3-激酶(PI3K)/AKT 非基因组 ER 信号转导至组蛋白甲基转移酶增强子的锌指蛋白 2(EZH2)。结果,这种前基因组信号转导磷酸化并抑制 EZH2,并降低染色质中 H3K27me3 抑制标记的水平。此外,只有染料木黄酮会导致成年子宫肌层中的雌激素反应基因对激素产生超反应性;暴露于双酚 A 的子宫中的雌激素反应基因被抑制。重要的是,EZH2 结合以减少而非增加 H3K27 甲基化的这种模式与这些外源性雌激素对肿瘤发生的影响相关。染料木黄酮的发育重编程促进了子宫平滑肌瘤的发展,增加了肿瘤的发生率和多发性,而双酚 A 则没有。这些数据表明,环境雌激素在发育中的子宫中具有不同的非基因组效应,这决定了它们结合表观遗传调节剂 EZH2 的能力,在发育重编程过程中降低染色质中抑制性表观遗传组蛋白 H3K27 甲基化标记的水平,并促进子宫肿瘤发生。