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）：在过去的三十年中，乳腺癌的发病率大大增加，与将激素模仿到环境中相吻合。据推测，发育性接触异源雌激素，尤其是双酚-A（BPA）可能是这种增加的因果因素。假设BPA在整个产前期（妊娠第9天之后）和产后（出生后第21天的出生）给药，通过雌激素受体介导的机制和/或通过影响DNA甲基化来改变雌激素反应基因的表达，从而导致乳腺癌的变化导致乳腺癌症状，从而导致乳腺癌的症状易变。将追求以下特定目标：目标1：确定BPA暴露导致乳腺癌发病率增加的水平。将检查两个易感性的窗户：从妊娠日（GD）9到出生，从GD9到断奶（产后日[PND21]）。在50天大的时候，将通过单个腹膜内剂量的致癌硝基甲基脲（NMU，20 mg/kg）或媒介物挑战大鼠。将测量肿瘤的发病率和潜伏期（n = 30大鼠/组的A水平为0.05，功率= 0.80）。将检查组织结构变化的时间顺序以及肿瘤前和肿瘤病变的出现。为了评估内部剂量，将在暴露期间测量大坝血液中的BPA水平。此外，将开发出暴露标记以增加检测剂量的范围。目标2：探索负责诱导BPA暴露引起的肿瘤变化的机制。组织结构的起源和维护涉及生物组织的几个层次。因此，这项研究将探索i）BPA暴露对mRNA表达的影响，ii）基因组DNA在基质和上皮中的甲基化模式，以及iii）iii）通过组织重组实验以及是否存在BPA核定病变和/或/或/或/或/或/或/或/或/或epitheal ressiast the tromal和上皮变化的作用。这项工作将立即并显着影响：1）基础科学：介导BPA的致癌作用的形态发生事件的揭示将指示组织结构在致癌中的核心作用，从而将癌症研究的重点转移到从组织和非含量型的组织水平到组织水平上的癌症事件，例如，诸如caine and and Mutagagenic Agents and Notmutagenic Agens and Cain and and Notmutagenic Ancent and ins and Mighordement and ins and Mytherment and诸如诸如神经素的群体。 2）公共政策：它将提供对BPA的风险评估所需的两个基本部分：乳腺中与环境相关的BPA暴露的致癌潜力的明确证据，以及将动物与人类暴露相比所需的内部剂量的测量。 3）医学实践：这将使医生意识到环境污染是疾病的原因，尤其是在与激素靶向器官的癌症打交道时。 公共卫生相关性：在过去的五十年中，人群中观察到的有害健康效应的增加，包括乳腺癌，不育和肥胖，对异种雌激素（例如BPA）的围产期暴露与有害健康效应的增加有关。我们观察到围产期暴露于低剂量BPA的动物发生了乳腺癌性病变。拟议的研究旨在确定围产期暴露于BPA和乳腺肿瘤之间的关联，并表征潜在的机制。这与对BPA的评估是最重要的，这是92％的美国人群中发现的广泛污染物，因此它有可能极大地影响公共卫生和公共卫生政策。