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

乳腺癌是从子宫​​里开始的吗？

• 批准号: 8074160
• 负责人: ANA SOTO
• 金额: $ 8.03万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-27 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074160
• 关键词: Adult; Affect; Age; American; Animals; Architecture; Basic Science; Biological; Birth; Blood; Candidate Disease Gene; Carcinogens; Chemicals; DNA; DNA Methylation; Detection; Development; Disease; Dose; Environment; Environmental Pollution; Epithelial; Epithelium; Estrogen Receptors; Estrogens; Evaluation; Event; Exposure to; Feasibility Studies; Fetus; Genes; Genomics; Health; Health Policy; Hormones; Human; Hyperplasia; In Situ Hybridization; Inbred WF Rats; Incidence; Infertility; Lesion; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Measurable; Measurement; Measures; Mediating; Medical; Metabolic; Methylation; Methylnitrosourea; Microarray Analysis; Multiparametric Analysis; Neoplasms; Obesity; Organ; Pattern; Perinatal Exposure; Physicians; Pilot Projects; Population; Predisposition; Premalignant; Process; Public Health; Public Policy; Pump; RNA; Rat Strains; Rattus; Recombinants; Research; Risk Assessment; Role; Route; Scientist; Serum Markers; Signal Transduction; Testing; Time; Tissue Recombination; Tissues; Transcript; Uterus; Weaning; Woman; Work; bisphenol A; carcinogenesis; exposed human population; falls; imprint; in utero; intraperitoneal; laser capture microdissection; lifetime risk; mRNA Expression; malignant breast neoplasm; metabolomics; morphogens; neoplastic; novel; postnatal; prenatal; public health relevance; research study; response; tumor; xenoestrogen

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.

描述（由申请人提供）：在过去三十年中，随着激素模拟物被引入环境，乳腺癌发病率大幅增加。据推测，发育过程中接触异雌激素，特别是双酚 A (BPA) 可能是导致这种增加的原因。据推测，在整个产前期（妊娠第 9 天之后）和产后期（出生到产后第 21 天）施用 BPA 会通过雌激素受体介导的机制和/或影响 DNA 甲基化来改变雌激素反应基因的表达，从而导致乳房生成发生改变，从而导致乳腺癌易感性增加。我们将追求以下具体目标： 目标 1：确定 BPA 暴露水平会导致乳腺癌发病率增加。将检查两个易感性窗口：从妊娠第 9 天到出生，以及从 GD9 到断奶（出生后第 1 天 [PND21]）。 50 天龄时，大鼠将接受单次腹膜内剂量的致癌物亚硝基甲基脲（NMU，20 mg/kg）或媒介物的攻击。将测量肿瘤发生率和潜伏期（n=30只大鼠/组，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，还将开发暴露标记以扩大检测剂量的范围。目标 2：探索 BPA 暴露引起肿瘤变化的机制。组织结构的发生和维持涉及多个层次的生物组织。因此，本研究将探讨 i) BPA 暴露对 mRNA 表达的影响，ii) 间质和上皮中基因组 DNA 的甲基化模式，以及 iii) 通过组织重组实验的间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 介导的间质和/或上皮改变所致。这项工作将立即产生重大影响：1）基础科学：解开介导 BPA 致癌作用的形态发生事件将表明组织结构在致癌作用中的核心作用，从而将癌症研究的焦点从发生在组织亚细胞水平的事件转移到组织的组织水平以及非诱变剂，例如形态发生素和激素，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要素：乳腺中与环境相关的 BPA 暴露具有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导致疾病的原因，特别是在治疗激素靶器官的癌症时。 公共卫生相关性：围产期接触 BPA 等异雌激素与过去 50 年来在人群中观察到的有害健康影响的增加有关，包括乳腺癌、不孕症和肥胖症。我们观察到，围产期接触低剂量 BPA 的动物会出现乳腺癌前病变。拟议的研究旨在确定围产期接触 BPA 与乳腺肿瘤之间的关联，并描述其潜在机制。这与 BPA 的评估密切相关，BPA 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。