Bromer Jason G, Wu Jie, Zhou Yuping, Taylor Hugh S
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
Endocrinology. 2009 Jul;150(7):3376-82. doi: 10.1210/en.2009-0071. Epub 2009 Mar 19.
Diethylstilbestrol (DES) is a nonsteroidal estrogen that induces developmental anomalies of the female reproductive tract. The homeobox gene HOXA10 controls uterine organogenesis, and its expression is altered after in utero DES exposure. We hypothesized that an epigenetic mechanism underlies DES-mediated alterations in HOXA10 expression. We analyzed the expression pattern and methylation profile of HOXA10 after DES exposure. Expression of HOXA10 is increased in human endometrial cells after DES exposure, whereas Hoxa10 expression is repressed and shifted caudally from its normal location in mice exposed in utero. Cytosine guanine dinucleotide methylation frequency in the Hoxa10 intron was higher in DES-exposed offspring compared with controls (P = 0.017). The methylation level of Hoxa10 was also higher in the caudal portion of the uterus after DES exposure at the promoter and intron (P < 0.01). These changes were accompanied by increased expression of DNA methyltransferases 1 and 3b. No changes in methylation were observed after in vitro or adult DES exposure. DES has a dual mechanism of action as an endocrine disruptor; DES functions as a classical estrogen and directly stimulates HOXA10 expression with short-term exposure, however, in utero exposure results in hypermethylation of the HOXA10 gene and long-term altered HOXA10 expression. We identify hypermethylation as a novel mechanism of DES-induced altered developmental programming.
己烯雌酚（DES）是一种非甾体雌激素，可诱发女性生殖道发育异常。同源框基因HOXA10控制子宫器官发生，子宫内暴露于DES后其表达会发生改变。我们推测一种表观遗传机制是DES介导的HOXA10表达改变的基础。我们分析了DES暴露后HOXA10的表达模式和甲基化谱。DES暴露后人子宫内膜细胞中HOXA10的表达增加，而在子宫内暴露的小鼠中，Hoxa10的表达受到抑制并从其正常位置向尾侧移位。与对照组相比，DES暴露后代中Hoxa10内含子中的胞嘧啶鸟嘌呤二核苷酸甲基化频率更高（P = 0.017）。DES暴露后，子宫尾侧部分Hoxa10在启动子和内含子处的甲基化水平也更高（P < 0.01）。这些变化伴随着DNA甲基转移酶1和3b表达的增加。体外或成年期DES暴露后未观察到甲基化变化。DES作为一种内分泌干扰物具有双重作用机制；DES作为一种经典雌激素发挥作用，短期暴露可直接刺激HOXA10表达，然而，子宫内暴露会导致HOXA10基因高甲基化并长期改变HOXA10表达。我们将高甲基化确定为DES诱导发育程序改变的一种新机制。
