In utero estrogenic exposures and transgenerational risk for breast cancer

描述(由申请人提供)： 子宫内雌激素暴露和乳腺癌的跨代风险背景：在人类和动物中的研究表明，孕妇在怀孕期间吃什么或暴露在什么环境中，可能会影响她的后代成年后对疾病的易感性。使用老鼠模型，我们之前已经证明，怀孕期间高脂肪的母亲饮食与怀孕雌激素水平的增加和女儿患乳腺癌的风险有关。最近，有研究表明，孕妇在怀孕期间暴露在什么环境中不仅会影响她的后代患某些疾病的风险，也会影响下一代的风险。这些效应被认为是通过表观遗传机制遗传的。目的/假设：我们建议研究孕鼠摄入高脂肪饮食或补充雌激素的饮食是否会影响后代和后续两代患乳腺癌的风险。我们假设，子宫内雌激素暴露会增加雌性后代(F1)患乳腺癌的风险，并将通过表观遗传机制传递给后代(F2/F3)。更好地了解宫内环境如何导致子代和后代乳腺癌风险的调节，可能对乳腺癌的预防具有重要意义。具体目标：(1)确定怀孕大鼠暴露于雌激素或高脂肪饮食是否与后代(F1)和后代(F2/F3)乳腺癌风险增加有关。(2)确定这些宫内暴露是否与后代(F1)和后代(F2/F3)乳腺发育生物学的变化有关。(3)确定这些在子宫暴露中的影响是否通过表观遗传机制传递给后代。研究设计：怀孕的SD大鼠将在妊娠期间接受高脂肪饮食或补充雌二醇的饮食，并将在后代中监测乳腺癌的发展(F1)。为了解决在后代中看到的表型是否会遗传给后代，我们将交配雌性和雄性后代(F1)，并检查下一代(F2)患乳腺癌的风险。同样，F2代将进行交配，并在后代(F3)中检查乳腺癌。我们将利用全基因组甲基化和微阵列研究，检查F1、F2和F3代乳腺癌表型是否与乳腺表观遗传学和基因表达模式的变化有关。我们还将检查乳腺形态，以评估乳腺发育的变化。

DESCRIPTION (provided by applicant): In utero estrogenic exposures and transgenerational risk for breast cancer Background: Research in humans and animals suggests that what an expecting mother eats or is exposed to during pregnancy, can affect her offspring's susceptibility to disease in adulthood. Using a rat model, we have previously shown that a maternal diet high in fat during pregnancy is associated with increase in pregnancy estrogen levels and breast cancer risk in daughters. More recently, it was shown that what an expecting mother is exposed to during pregnancy affects risk of certain diseases not only in her offspring but subsequent generations as well. These effects are thought to be inheritable through epigenetic mechanisms. Objective/ hypothesis: We propose to study whether exposing pregnant rats to a high fat diet or an estrogen- supplemented diet will affect the risk of mammary cancer in the offspring and two subsequent generations. We hypothesize that in utero estrogenic exposures will increase the risk of mammary cancer of the female offspring (F1) and will be transmitted to the subsequent generations (F2/F3) through epigenetic mechanisms. A better understanding of how the in utero environment leads to modulation of breast cancer risk in the offspring and subsequent generations could have great implications for breast cancer prevention. Specific Aims: (1) Determine whether exposure of pregnant rats to estrogens or a high-fat diet is associated with increased mammary cancer risk in the offspring (F1) and subsequent generations(F2/F3). (2) Determine whether these in utero exposures are associated with changes in mammary gland developmental biology in the offspring (F1) and subsequent generations (F2/F3). (3) Determine whether the effects of these in utero exposures are transmitted to subsequent generations through epigenetic mechanisms. Study Design: Pregnant Sprague-Dawley rats will receive a high fat diet or an estradiol supplemented diet during gestation and mammary cancer development will be monitored in the offspring (F1). To address if the phenotype seen in the offspring is passed to subsequent generations, we will mate the female and male offspring (F1) and examine mammary cancer risk in the next generation (F2). Similarly, the F2 generation will be mated and mammary cancer examined in the offspring (F3). We will examine whether the mammary cancer phenotype in the F1, F2 and F3 generations is associated with changes in epigenetic and gene expression patterns in the mammary gland, employing genome-wide methylation and microarrays studies. We will also examine the mammary gland morphology to assess changes in mammary gland development.