Environmental Epigenetics and Stem/Progenitor Cell Injury

环境表观遗传学和干/祖细胞损伤

• 批准号: 7627360
• 负责人: Tim H.-M. Huang
• 金额: $ 37.9万
• 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/7627360
• 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; 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; 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; breast tumorigenesis; 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）： 环境暴露于内分泌干扰剂或异种雌激素会增加患乳腺癌的风险。动物和人群研究表明，一种烙印现象，从而早期暴露于异雌激素会导致生命后期的肿瘤发生。这些环境压力源可以转化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以CpG岛高甲基化的形式将表观遗传学改变传递到预先暴露于异种雌激素的未分化细胞的后代。具体而言，我们提出，人乳房的茎/祖细胞室中的未成熟细胞是这种环境损伤的主要目标。 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在这些启动子上添加DNA甲基转移酶的启动子岛，这是由于局部甲基转移酶活性增加的结果，这标志着特定的基因沉默3，我们将在临床上的摩尔群中表现出CPG岛的高度甲基化。在这方面，表现出这种表观遗传的患者可能会在正常的哺乳动物上皮中出现这些甲基化的变化，从而使人们的乳房中的癌症在这种类型的癌症中，因此，在这类型的癌症中可能会在这类癌症中，在这类型的癌症中可能会在这种情况下，在这类甲基化的情况下可能会在这种类型的癌症中，因此，异源性的表观植物可能会在这种类型的情况下使用，在这方面，异内型的表观植物可能会在这类型的实验中使用，这可能是在这类型的乳腺上，因此在这方面，异源性的表观植物可能会在这类型的情况下，在这类型的乳房中可能会在这类型的情况下，在这方面，异内型的表观植物可能会在这类型的情况下，在这类型的乳腺上可能会出现，而在这类型的乳腺癌中，则表现出较低的甲基化变化。进一步的模型，从异源性造成的乳腺肿瘤发生的历史，从肿瘤前病变到增生到原位癌的癌症，再到临床癌的特异性。检测，是环境雌激素的假定生物传感器。