Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA.
Present Address: Reproductive Medicine Center of Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China, 450003.
BMC Biol. 2022 May 2;20(1):93. doi: 10.1186/s12915-022-01293-4.
Estriol (E) is a steroid hormone formed only during pregnancy in primates including humans. Although E is synthesized at large amounts through a complex pathway involving the fetus and placenta, it is not required for the maintenance of pregnancy and has classically been considered virtually inactive due to associated very weak canonical estrogen signaling. However, estrogen exposure during pregnancy may have an effect on organs both within and outside the reproductive system, and compounds with binding affinity for estrogen receptors weaker than E have been found to impact reproductive organs and the brain. Here, we explore potential effects of E on fetal development using mouse as a model system.
We administered E to pregnant mice, exposing the fetus to E. Adult females exposed to E in utero (E-mice) had increased fertility and superior pregnancy outcomes. Female and male E-mice showed decreased anxiety and increased exploratory behavior. The expression levels and DNA methylation patterns of multiple genes in the uteri and brains of E-mice were distinct from controls. E promoted complexing of estrogen receptors with several DNA/histone modifiers and their binding to target genes. E functions by driving epigenetic change, mediated through epigenetic modifier interactions with estrogen receptors rather than through canonical nuclear transcriptional activation.
We identify an unexpected functional role for E in fetal reproductive system and brain. We further identify a novel mechanism of estrogen action, through recruitment of epigenetic modifiers to estrogen receptors and their target genes, which is not correlated with the traditional view of estrogen potency.
雌三醇（E）是一种甾体激素，仅在灵长类动物（包括人类）的怀孕期间形成。尽管 E 通过涉及胎儿和胎盘的复杂途径大量合成，但由于相关的非常弱的经典雌激素信号，它对于维持妊娠并非必需，并且通常被认为几乎没有活性。然而，怀孕期间的雌激素暴露可能对生殖系统内外的器官都有影响，并且已经发现与 E 结合亲和力较弱的化合物会影响生殖器官和大脑。在这里，我们使用小鼠作为模型系统来探索 E 对胎儿发育的潜在影响。
我们给怀孕的小鼠施用 E，使胎儿暴露于 E 中。在子宫内暴露于 E 的成年雌性（E-小鼠）具有更高的生育能力和更好的妊娠结局。雌性和雄性 E-小鼠表现出焦虑减少和探索行为增加。E-小鼠的子宫和大脑中的多个基因的表达水平和 DNA 甲基化模式与对照组不同。E 促进雌激素受体与几种 DNA/组蛋白修饰剂的复合，并与靶基因结合。E 通过与雌激素受体相互作用的表观遗传修饰剂介导的表观遗传变化发挥作用，而不是通过经典的核转录激活。
我们确定了 E 在胎儿生殖系统和大脑中的意想不到的功能作用。我们进一步确定了雌激素作用的一种新机制，即通过招募表观遗传修饰剂到雌激素受体及其靶基因，这与传统的雌激素效力观点无关。
Zotero 插件
