Environmental Epigenetics and Stem/Progenitor Cell Injury

环境表观遗传学和干/祖细胞损伤

• 批准号: 7485195
• 负责人: Tim H.-M. Huang
• 金额: $ 36.79万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485195
• 关键词: Adult; Animal Model; Binding; Biological Assay; Biological Markers; Biosensor; Breast; Breast Cancer Early Detection; Cancer Patient; Cancerous; Carcinoma; Carcinoma in Situ; Cell Differentiation process; Cell model; Cells; Chemical Exposure; Chemicals; Chromatin; Clinical; Clinical Sensitivity; CpG Islands; DMA-methyltransferase; DNA Methyltransferase; DNA Modification Methylases; Data; Development; Diethylstilbestrol; Disease; Endocrine; Endocrine Disruptors; Environmental Estrogen; Environmental Exposure; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Estradiol; Estrogen Receptors; Estrogens; Event; Exhibits; Exposure to; Future; Gene Silencing; Genes; Genetic Transcription; Genome; Growth; Homeostasis; Human; Hypermethylation; Hyperplasia; In Vitro; Individual; Injury; Invasive; Laboratories; Lead; Left; Lesion; Life; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Memory; Methylation; Methyltransferase; Microarray Analysis; Modeling; Molecular; Normal tissue morphology; Patients; Pattern; Play; Polycomb; Polymerase Chain Reaction; Primary Neoplasm; Procedures; Process; Proteins; Recording of previous events; Recruitment Activity; Research Personnel; Risk; Role; Sample Size; Sampling; Screening procedure; Sensitivity and Specificity; Series; Signal Transduction; Stem cells; Structure; System; Testing; Tissue Sample; Tumor Suppressor Genes; Undifferentiated; Xenograft Model; animal population study; base; bisphenol A; bisulfite; cancer risk; cell injury; environmental stressor; imprint; interest; malignant breast neoplasm; mammary epithelium; mathematical model; neoplastic; progenitor; programs; promoter; stem; tumorigenesis; xenoestrogen

DESCRIPTION (provided by applicant): Environmental exposure to endocrine-disrupting agents, or xenoestrogens, can increase the risk of developing breast cancer. Animal and population studies suggest an imprinting phenomenon whereby early exposure of xenoestrogen can lead to tumorigenesis later in life. The molecular mechanism by which these environmental stressors can transform breast genomes is not well understood. Our preliminary data prompt us to hypothesize that epigenetic alteration, in the form of CpG island hypermethylation, transmits this imprinted information to the progeny of undifferentiated cells pre-exposed to xenoestrogens. Specifically, we propose that immature cells located in the stem/progenitor compartment of the human breast are prime targets of this environmental insult. In Specific Aim 1, primary breast stem/progenitor cells will be exposed to xenoestrogens - diethylstilbestrol, bisphenol A, or 17(3-estradiol in an in vitro system. 'Global analysis is expected to identify altered methylation status in 1-2% of ~29,000 CpG islands analyzed. These epigenetic events can be the direct results of exposing stem/progenitor cells to xenoestrogens. The epigenetic memory of this injury is then transmitted to differentiated epithelial cells and in turn leads to breast tumorigenesis in a xenograft model. In Specific Aim 2, we will functionally determine whether the prolonged exposure of these endocrine chemicals to stem/progenitor cells disrupt the homeostasis of estrogen signaling and triggers an epigenetic cascade in its downstream targets. Polycomb repressors can be recruited to promoter CpG islands followed by the addition of DNA methyltransferases at these promoters. Acquired DMA methylation, as a result of increased local methyltransferase activities, marks the heritable gene silencing. In Specific Aim 3, we will demonstrate that CpG island hypermethylation induced by xenoestrogen exposure is also observed in clinical samples. The presence of these molecular alterations in primary breast tumors may constitute a xenoestrogen epigenotype(s). In this regard, patients exhibiting this epigenotype are likely exposed to xenoestrogens in their early lives. In addition, low levels of these methylation changes may exist in normal looking mammary epithelial, leaving a field of cancerization in the human breast. This type of CpG island hypermethylation can be tracked as molecular relics using a mathematical modeling approach developed in our laboratory. We will develop the model further to recreate the history of xenoestrogen- induced breast tumorigenesis, from pre-neoplastic lesions to hyperplasia to carcinoma in situ to invasive carcinoma. Clinical sensitivity and specificity of potential CpG island loci pinpointing the xenoestrogen epigenotype will be provided as a quantitative milestone for this U01 project. These loci are future biomarkers for early breast cancer detection and are putative biosensors to environmental estrogens.

描述（由申请人提供）： 环境中暴露于内分泌干扰剂或异雌激素会增加患乳腺癌的风险。动物和群体研究表明，早期接触异雌激素可能导致晚年肿瘤发生，这是一种印记现象。这些环境压力因素改变乳腺基因组的分子机制尚不清楚。我们的初步数据促使我们假设表观遗传改变（以 CpG 岛高甲基化的形式）将这种印记信息传递给预先暴露于异种雌激素的未分化细胞的后代。具体来说，我们认为位于人类乳房干/祖细胞室中的未成熟细胞是这种环境损害的主要目标。在具体目标 1 中，原代乳腺干细胞/祖细胞将在体外系统中暴露于异雌激素 - 己烯雌酚、双酚 A 或 17(3-雌二醇)。“全球分析预计将识别 1-2% 的乳腺干细胞/祖细胞中甲基化状态的改变。分析了约 29,000 个 CpG 岛，这些表观遗传事件可能是干细胞/祖细胞暴露于异雌激素的直接结果。然后，这种损伤传递到分化的上皮细胞，进而导致异种移植模型中的乳腺肿瘤发生。在具体目标 2 中，我们将在功能上确定这些内分泌化学物质长期暴露于干细胞/祖细胞是否会破坏雌激素信号传导的稳态。并在其下游靶标中触发表观遗传级联反应，可以将 Polycomb 阻遏物招募到启动子 CpG 岛，然后在这些启动子上添加 DNA 甲基转移酶。 DMA 甲基化是局部甲基转移酶活性增加的结果，标志着可遗传的基因沉默。在具体目标 3 中，我们将证明在临床样本中也观察到由​​异雌激素暴露引起的 CpG 岛高甲基化。原发性乳腺肿瘤中这些分子改变的存在可能构成异雌激素表观基因型。在这方面，表现出这种表观基因型的患者可能在早年接触过异雌激素。此外，这些甲基化变化的低水平可能存在于看起来正常的乳腺上皮中，从而在人类乳房中留下癌变区域。这种类型的 CpG 岛高甲基化可以使用我们实验室开发的数学建模方法作为分子遗迹进行追踪。我们将进一步开发该模型，以重建异雌激素诱导的乳腺肿瘤发生的历史，从肿瘤前病变到增生，再到原位癌再到浸润性癌。确定异雌激素表观基因型的潜在 CpG 岛位点的临床敏感性和特异性将作为该 U01 项目的定量里程碑。这些基因座是未来早期乳腺癌检测的生物标志物，并且是环境雌激素的假定生物传感器。