Environmental Estrogens and Uterine Leiomyoma

描述（由申请人提供）：在发育的关键、敏感时期不适当地暴露于环境因子，可通过表观遗传机制重新编程靶组织，增加成年后的疾病风险。生殖道对这种类型的发育编程特别敏感，以应对异雌激素暴露，这是一种普遍存在于我们环境中的主要内分泌干扰化学品。我们最近的研究表明，新生儿暴露于外源性雌激素后，子宫肌层中雌激素反应基因对激素的反应性增加，从而增加了发生子宫内膜依赖性平滑肌瘤的风险。虽然负责发育编程的表观遗传机制是未知的，但最近的数据表明，一种类型的表观遗传修饰，组蛋白甲基化，响应于通过AKT磷酸化组蛋白甲基转移酶激活PI3K信号而改变。由于雌激素可以通过非基因组信号转导激活PI3K，我们假设，外源性雌激素，通过激活细胞信号转导途径，可以修改组蛋白甲基转移酶的活性，导致表观遗传改变组蛋白甲基化模式，有助于在子宫发育编程。为了验证这一假设，我们提出了以下具体目标：具体目标1：测试的假设，雌激素激活细胞信号的变化，改变基因表达的组蛋白修饰的结果。具体目标二：确定AKT或ERK对甲基转移酶的磷酸化是否是雌激素引起组蛋白修饰变化的原因。具体目标3：确定组蛋白修饰对子宫中基因表达的发育编程的贡献。这些研究将探索激活细胞信号作为一种新的机制，组蛋白甲基转移酶活性可以通过雌激素调节，导致组蛋白甲基化模式的表观遗传改变。此外，他们将确定新生儿暴露于异种雌激素诱导的组蛋白甲基化的变化是否是可遗传的，并通过调节成年动物的基因表达来促进发育编程。 公共卫生相关性：子宫平滑肌瘤是最常见的妇科肿瘤的妇女，他们有一个巨大的负面影响，对健康的数百万妇女在美国。令人惊讶的是，我们对导致这些肿瘤的原因知之甚少，尽管激素，包括环境雌激素，与这种疾病的病因有关。我们提出，环境雌激素可能有助于这些肿瘤的发展的一个潜在机制是通过发育编程。在这个应用程序中，我们将测试的假设，即在子宫的发展，暴露于环境雌激素重新编程基因表达的子宫肌层，这些肿瘤的发展在以后的生活中。我们提出这种重编程的机制是激活非基因组信号通路来调节组蛋白甲基转移酶的活性，并诱导组蛋白甲基化的表观遗传模式发生改变。

DESCRIPTION (provided by applicant): Inappropriate exposure to environmental agents during critical, sensitive periods of development can reprogram target tissues via epigenetic mechanisms to increase the risk for disease later in adult life. The reproductive tract is particularly sensitive to this type of developmental programming in response to xenoestrogen exposure, a major class of endocrine disrupting chemicals that are ubiquitously present in our environment. We have recently shown that developmental programming following neonatal xenoestrogen exposure can increase the risk of developing hormone-dependent leiomyoma by increasing the responsiveness to hormone of estrogen-responsive genes in the myometrium. Although the epigenetic mechanism(s) responsible for developmental programming are unknown, recent data indicate that one type of epigenetic modification, histone methylation, is altered in response to activation of PI3K signaling via phosphorylation of histone methyltransferases by AKT. Since estrogens can activate PI3K via nongenomic signaling, we hypothesize that xenoestrogens, via activation of cell signaling pathways, can modify the activity of histone methyltransferases, leading to epigenetic alterations in histone methylation patterns that contribute to developmental programming in the uterus. To test this hypothesis, we propose the following Specific Aims: Specific Aim 1: Test the hypothesis that estrogen-activation of cell signaling results in changes in histone modifications that alter gene expression. Specific Aim 2: Determine if phosphorylation of methyltransferases by AKT or ERK is responsible for changes in histone modifications that occur in response to estrogens. Specific Aim 3: Determine the contribution of histone modifications to developmental programming of gene expression in the uterus. These studies will explore activation of cell signaling as a novel mechanism by which histone methyltransferase activity can be modulated by estrogens, resulting in epigenetic alterations in histone methylation patterns. In addition, they will determine if changes in histone methylation induced by neonatal exposure to xenoestrogens are heritable and contribute to developmental programming by modulating gene expression in adult animals. PUBLIC HEALTH RELEVANCE: Uterine leiomyoma are the most common gynecologic tumor of women and they have a tremendous negative effect on the health of millions of women in the US. Surprisingly, we know very little about what causes these tumors, although hormones, including environmental estrogens, have been implicated in the etiology of this disease. We propose that a potential mechanism by which environmental estrogens may contribute to the development of these tumors is through developmental programming. In this application we will test the hypothesis that during development of the uterus, exposure to environmental estrogens reprograms gene expression in the myometrium to predispose to the development of these tumors later in life. The mechanism that we propose for this reprogramming is the activation of nongenomic signaling pathways to modulate the activity of histone methyltransferases and induce alterations in epigenetic patterns of histone methylation.