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

描述（由申请人提供）：乳腺癌发病率在过去三十年中大幅增加，与激素模拟物引入环境相一致。据推测，发育期暴露于异种雌激素，特别是双酚A（BPA）可能是导致这种增加的原因。据推测，在整个产前（妊娠第9天以后）和产后（出生至产后第21天）期间给予BPA通过雌激素受体介导的机制和/或通过影响DNA甲基化改变了雌激素应答基因的表达，这反过来又导致乳腺发生改变，从而增加了对乳腺癌的易感性。将追求以下具体目标：目标1：确定BPA暴露导致乳腺癌发病率增加的水平。将检查两个敏感性窗口：从妊娠第9天（GD）至出生，以及从GD 9至断奶（出生后第21天[PND]）。在50日龄时，将用单次腹膜内给药致癌物亚硝基甲基脲（NMU，20 mg/kg）或溶剂对大鼠进行激发。测量肿瘤发生率和潜伏期（n=30只大鼠/组，a水平为0.05，功效=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。为了评估内部剂量，将在暴露期间测量母鼠血液中的BPA水平。此外，还将开发一种暴露标记物，以增加检测剂量的范围。目的2：探讨BPA暴露诱导肿瘤变化的机制。组织结构的发生和维持涉及几个层次的生物组织。因此，本研究将探索i）BPA暴露对mRNA表达的影响，ii）基质和上皮中基因组DNA的甲基化模式，iii）通过组织重组实验研究基质和上皮改变的作用，以及肿瘤前病变的存在是否是由于BPA介导的基质和/或上皮改变。这项工作将立即产生重大影响：1）基础科学：介导BPA致癌作用的形态发生事件的解开将标志着组织结构在致癌作用中的中心作用，从而将癌症研究的重点从组织的亚细胞水平转移到组织的组织水平和非诱变剂，如形态发生剂和激素，作为重要的致病因素。2)公共政策：它将提供BPA风险评估所需的两个基本部分：乳腺中环境相关BPA暴露致癌潜力的明确证据，以及比较动物与人类暴露所需的内部剂量测量。3)医疗实践：它将使医生意识到环境污染是疾病的一个原因，特别是在处理目标器官中的癌症时。 公共卫生相关性：在过去的五十年里，围产期暴露于BPA等异种雌激素与在人群中观察到的有害健康影响的增加有关，包括乳腺癌、不育和肥胖。我们观察到围产期暴露于低剂量BPA的动物出现乳腺癌前病变。该研究旨在确定围产期暴露于BPA和乳腺肿瘤之间的关联，并描述其潜在机制。这对BPA的评估至关重要，BPA是一种广泛存在的污染物，在92%的受试美国人口中发现，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.