Effect of bisphenol A exposure on mammary stem cell function and transformation

双酚A暴露对乳腺干细胞功能和转化的影响

• 批准号: 8664849
• 负责人: LUZHE SUN
• 金额: $ 33.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-23 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664849
• 关键词: Adverse effects; Affect; Animals; Beverages; Breast Cancer Risk Factor; Callithrix; Callithrix jacchus jacchus; Carcinoma in Situ; Cell Count; Cell physiology; Cell surface; Chemicals; DNA Damage; DNA Repair; Development; Diet; Dose; Epoxy Resins; Exposure to; Food; Frequencies; Gene Expression Profile; Growth; Human; Incidence; Intraductal Hyperplasia; Ionizing radiation; Laboratories; Lead; Life; Light; Link; Longevity; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Morphogenesis; Mus; Neoplastic Cell Transformation; Obese Mice; Obesity; Perinatal Exposure; Phylogenetic Analysis; Physiological; Pit and Fissure Sealants; Play; Predisposition; Pregnancy; Primates; Puberty; Radiation Induced DNA Damage; Research; Right-On; Risk; Risk Factors; Rodent; Rodent Model; Role; Signal Transduction; Simulate; Staging; Stem cells; Testing; Time; Tissue Sample; Tumor Suppressor Genes; bisphenol A; cell growth; cell transformation; disorder prevention; in vitro Assay; innovation; interest; irradiation; malignant breast neoplasm; mammary gland development; mouse model; neoplastic; neoplastic cell; nonhuman primate; novel; polycarbonate plastic; self-renewal; stem cell niche; steroid hormone receptor; tumorigenesis; xenoestrogen

DESCRIPTION (provided by applicant): Exposure to environmental synthetic estrogens, such as bisphenol A (BPA), has been implicated to contribute to the increasing incidence of breast cancer. Bisphenol A is a most pervasive chemical in modern life as a component of polycarbonate plastics and epoxy resins used widely for food and beverage containers and dental sealants. Perinatal exposure to low, environmentally relevant doses of BPA in rodents resulted in induction of preneoplastic ductal hyperplasias, carcinoma in situ, and increased susceptibility to tumorigenesis. However, the underlying mechanism for these observations is unclear. The murine mammary stem cells (MaSCs) have the potential to drive mammary gland development during puberty, and growth and remodeling during pregnancy. Recent lineage tracing studies also indicated the presence of a hierarchy of stem cells in the murine mammary gland. Significantly, these distinct unipotent basal and luminal MaSCs have been matched with different subtypes of breast cancer by their specific gene-expression signatures. Furthermore, modulation of oncogenes and tumor suppressors has been shown to increase stem cell compartment and self-renewal function of MaSCs, suggesting that alteration of MaSC frequency and function may lead to transformation and tumorigenesis. Unpublished results indicate that low dose BPA exposure during puberty can alter the number of different lineage MaSCs. Recent animal studies showed that BPA also promoted tumor cell growth through estrogenic signaling implicating the risk of development and progression of mammary cancer by BPA exposure at various time points throughout the lifespan. Thus it is hypothesized that mammary gland exposed to BPA at a susceptible window may lead to its susceptibility to tumorigenesis through a MaSC and/or stem cell niche mediated mechanism. In addition to mice, the intent is to also use common marmoset to determine the effect of BPA on its MaSC function and transformation because nonhuman primates, with their close phylogenetic relationship to humans, can better simulate the effects of physiological and pathological factors on humans. This hypothesis will be tested with three specific aims. First, the effect of BPA will be determined on MaSC function of non-primate and primate subjects. A novel in vitro assay developed in this laboratory will be exploited, instead of cell surface markers that are not specific for MaSCs, to quantify the alteration of basal and luminal MaSC number after systemic BPA treatment in various developmental windows of the mammary gland of mice and marmoset. Second, a determination of the effect of low dose irradiation on the transformation potential of MaSCs derived from BPA-exposed mice will be accomplished. The hypothesis to be tested for this specific aim is that the transforming activity of BPA may be more evident in combination with a DNA damaging agent such as ionizing radiation, which is a known risk factor for breast cancer. Third, the effect of BPA treatment on MaSC function of obese mice and marmosets will be examined. This proposed research will not only answer the question of whether BPA- induced morphogenesis changes in different developmental windows of mammary gland has a stem cell origin, but also shed light on MaSC susceptibility to multiple risk factor-induced cell transformation such as xenoestrogens, irradiation, and obesity, which will have important implications in disease prevention for human breast cancer.

描述（由申请人提供）：暴露于环境合成雌激素，如双酚A（BPA），可能导致乳腺癌发病率增加。 双酚A是现代生活中最普遍的化学品，作为广泛用于食品和饮料容器以及牙科密封剂的聚碳酸酯塑料和环氧树脂的组分。 围产期暴露于低，环境相关剂量的BPA的啮齿动物导致诱导癌前导管增生，原位癌，并增加易感性肿瘤发生。 然而，这些观察结果的潜在机制尚不清楚。小鼠乳腺干细胞（MaSCs）具有在青春期期间驱动乳腺发育以及在妊娠期间驱动生长和重塑的潜力。 最近的谱系追踪研究也表明在小鼠乳腺中存在干细胞层次。 值得注意的是，这些独特的单能基底和管腔MaSC通过其特异性基因表达特征与乳腺癌的不同亚型相匹配。 此外，癌基因和肿瘤抑制因子的调节已显示出增加MaSC的干细胞区室和自我更新功能，表明MaSC频率和功能的改变可能导致转化和肿瘤发生。未发表的结果表明，青春期低剂量BPA暴露可以改变不同谱系MaSCs的数量。最近的动物研究表明，BPA还通过雌激素信号促进肿瘤细胞生长，暗示在整个生命周期的不同时间点暴露于BPA会导致乳腺癌发展和进展的风险。 因此，假设乳腺在易感窗口暴露于BPA可能导致其通过MaSC和/或干细胞小生境介导的机制对肿瘤发生易感。除小鼠外，目的还在于使用普通绒猴来确定BPA对其MaSC功能和转化的影响，因为非人灵长类动物与人类的亲缘关系密切，可以更好地模拟生理和病理因素对人类的影响。将以三个具体目标来检验这一假设。一是 将确定BPA对非灵长类动物和灵长类动物受试者MaSC功能的影响。将利用本实验室开发的一种新的体外测定法，而不是细胞表面标记物， 不是MaSC特异性的，以量化小鼠和绒猴乳腺的各种发育窗口中全身BPA处理后基础和管腔MaSC数量的变化。其次，将完成低剂量辐射对源自BPA暴露小鼠的MaSC的转化潜力的影响的测定。为这一特定目的而测试的假设是，BPA的转化活性在与DNA损伤剂如电离辐射组合时可能更明显，电离辐射是乳腺癌的已知风险因素。第三，将检查BPA处理对肥胖小鼠和绒猴的MaSC功能的影响。这项拟议的研究不仅将回答BPA诱导的乳腺不同发育窗口中的形态发生变化是否具有干细胞起源的问题，而且还揭示了MaSC对多种风险因素诱导的细胞转化的易感性，如异种雌激素，辐射和肥胖，这将对人类乳腺癌的疾病预防具有重要意义。