Does breast cancer start in the womb? BPA, mammogenesis and neoplasia

描述(由申请人提供)：在过去的三十年中，乳腺癌的发病率大幅增加，这与荷尔蒙模拟物引入环境相吻合。据推测，发育过程中暴露于异种雌激素，特别是双酚A(BPA)可能是导致这种增加的原因。假设双酚A通过雌激素受体介导的机制和/或通过影响DNA甲基化改变雌激素反应基因的表达，进而导致乳腺发生改变，从而增加乳腺癌的易感性。将实现以下具体目标：目标1：确定双酚A暴露导致乳腺癌发病率增加的水平。将检查两个易感性窗口：从妊娠第9天(GD)到出生，以及从GD9到断奶(出生后第1天[PND21])。在50天龄时，大鼠将被单次腹腔注射致癌物质亚硝基甲基脲(NMU，20 mg/kg)或赋形剂。测量肿瘤发生率和潜伏期(n=30只大鼠/组，a水平为0.05，Power=0.80)。将检查组织结构变化的时间进程以及肿瘤前病变和肿瘤病变的出现。为了评估内照射剂量，将在暴露期间测量大坝血液中的双酚A水平。此外，还将开发一个暴露标记，以增加检测到的剂量范围。目的2：探讨双酚A暴露诱发肿瘤改变的机制。组织结构的发生和维持涉及生物组织的几个层次。因此，本研究将探讨：1)双酚A暴露对mRNA表达的影响；2)间质和上皮中基因组DNA的甲基化模式；3)通过组织重组实验研究间质和上皮改变的作用，以及癌前病变的存在是否是由双酚A介导的间质和/或上皮改变引起的。这项工作将立即和重大地影响：1)基础科学：介导双酚A致癌作用的形态致癌事件的解体将发出组织结构在致癌中的中心作用的信号，从而将癌症研究的重点从发生在亚细胞组织水平的事件转移到组织水平，并转移到作为重要致病因素的非诱变剂，如形态诱变剂和激素。2)公共政策：它将提供双酚A风险评估所需的两个基本要素：明确的证据表明与环境相关的双酚A在乳腺中的致癌潜力，以及比较动物和人类暴露所需的内部剂量。3)医疗实践：它将使医生意识到环境污染是疾病的原因，特别是在处理荷尔蒙靶标器官的癌症时。 公共卫生相关性：围产期暴露于异种雌激素，如双酚A，与过去50年中观察到的对人类健康有害影响的增加有关，包括乳腺癌、不孕和肥胖。我们观察到，围产期暴露于低剂量双酚A的动物会出现乳腺癌前病变。这项拟议的研究旨在确定围产期暴露于双酚A和乳腺肿瘤之间的联系，并表征其潜在的机制。这与对双酚A的评估极其相关，双酚A是一种广泛存在于92%的受测美国人口中的污染物，因此它有可能极大地影响公共卫生和公共卫生政策。

DESCRIPTION (provided by applicant): Breast cancer incidence has increased substantially during the last three decades, coinciding with the introduction of hormone mimics into the environment. It has been postulated that developmental exposure to xenoestrogens and in particular to bisphenol-A (BPA) may be the causal agent underlying this increase. It is hypothesized that BPA administered throughout the prenatal period (beyond gestational day 9) and postnatal period (birth to postnatal day 21) alters the expression of estrogen-responsive genes through estrogen receptor mediated mechanisms and/or by affecting DNA methylation, which in turn results in altered mammogenesis leading to an increased susceptibility to breast cancer. The following Specific Aims will be pursued: Aim 1: To determine the levels at which BPA exposure results in an increased incidence of mammary cancer. Two windows of susceptibility will be examined: from gestational day (GD) 9 to birth, and from GD9 to weaning (postnatal day [PND21]). At 50 days of age, rats will be challenged with a single intraperitoneal dose of the carcinogen nitrosomethylurea (NMU, 20 mg/kg) or vehicle. Tumor incidence and latency period will be measured (n=30 rats/group for an a level of 0.05 and power=0.80). The time-course of histoarchitectural changes and emergence of pre-neoplastic and neoplastic lesions will be examined. To assess the internal dose, BPA levels in blood of dams will be measured during the exposure period. Additionally, a marker of exposure will be developed to increase the range of detected doses. Aim 2: To explore mechanisms responsible for the induction of neoplastic changes due to BPA exposure. The genesis and maintenance of tissue architecture involves several levels of biological organization. Thus, this study will explore i) BPA exposure effects on mRNA expression, ii) the methylation pattern of genomic DNA both in the stroma and epithelium, and iii) the role of stromal and epithelial alterations by means of tissue recombination experiments and whether the presence of pre-neoplastic lesions is due to BPA-mediated stromal and/or epithelial alterations. This work will immediately and significantly impact: 1) Basic science: The unraveling of the morphogenic events that mediate the carcinogenic effect of BPA will signal the central role of tissue architecture in carcinogenesis, and thus switch the focus of research in cancer from events occurring at the subcellular level of organization to the tissue level of organization and to non-mutagenic agents, such as morphogens and hormones, as important causal agents. 2) Public policy: It will provide two essential pieces needed for risk assessment of BPA: unequivocal evidence of the carcinogenic potential of environmentally relevant BPA exposure in the mammary gland, and measurements of internal dose needed to compare animal with human exposures. 3) Medical Practice: It will make physicians aware of environmental pollution as a cause of diseases, particularly when dealing with cancers in hormone-target organs. PUBLIC HEALTH RELEVANCE: Perinatal exposure to xenoestrogens such as BPA is associated with the increase in deleterious health effects observed in human populations during the last fifty years, including breast cancer, infertility and obesity. We observed that animals exposed perinatally to low doses of BPA developed mammary precancerous lesions. The proposed study aims at identifying the association between perinatal exposure to BPA and mammary tumors and characterizing the underlying mechanisms. This is of utmost relevance to the evaluation of BPA, a widespread contaminant found in 92% of the tested American population and therefore it has the potential to greatly impact public health and public health policy.