Mechanism of developmental toxicity of Bisphenol-A

双酚A的发育毒性机制

• 批准号: 8473213
• 负责人: ANA SOTO
• 金额: $ 58.25万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8473213
• 关键词: Adult; Adverse effects; Agonist; American; Animals; Apoptosis; Atomic Force Microscopy; Biochemical; Biomechanics; Brain region; Breast; Breast Cancer Risk Factor; Carcinoma in Situ; Complex; Data; Daughter; Development; Diethylstilbestrol; Distal; Dose; Ductal; Endocrine Disruptors; Environment; Epithelium; Estrogen Receptors; Estrogens; Estrus; Evaluation; Exposure to; Extracellular Matrix; Fatty acid glycerol esters; Fetal Development; Gene Expression; Gland; Goals; Gonadotropins; Health; Health Policy; Hormonal; Hormones; Human; Hyperplasia; Hypothalamic structure; In Vitro; Incidence; Infertility; Intraductal Hyperplasia; Knowledge; Lactation; Lead; Lesion; Life; Link; Malignant Neoplasms; Mammary gland; Mediating; Mesenchymal; Mesenchyme; Methods; Modeling; Molecular; Morphogenesis; Mus; Neoplasms; Neoplastic Cell Transformation; Noninfiltrating Intraductal Carcinoma; Obesity; Organogenesis; Outcome; Ovarian hormone; Pathology; Perinatal; Perinatal Exposure; Periodicity; Phenotype; Pituitary Gland; Population; Pregnancy; Premalignant; Prevalence; Process; Property; Public Health; Research; Rodent; Role; Signal Transduction; Testing; Time; Tissues; Toxic effect; Transplantation; Woman; Work; anticancer research; bisphenol A; brain behavior; carcinogenicity; exposed human population; fetal; fetus cell; hypothalamic pituitary ovarian axis; innovation; lipid biosynthesis; malignant breast neoplasm; mammary gland development; neoplastic; physical property; programs; reproductive; reproductive success; research study; scaffold; success; tool; toxicant; tumor progression; xenoestrogen

DESCRIPTION (provided by applicant): Developmental exposure to bisphenol-A (BPA) at doses within the range of human exposure causes a complex array of adverse effects in animals. These outcomes are also known to be present in human populations and the rise in their occurrence coincides with the massive use of BPA and other endocrine disrupting chemicals in consumer goods. The main hormonal activity of BPA is as an estrogen mimic. Exposure to estrogens throughout a woman's life, including the period of fetal development, is considered a main risk factor for breast cancer. Developmental exposure to BPA altered mammary gland morphogenesis in rodents during the period of exposure and led to the development of pre-neoplastic and neoplastic lesions appearing in adulthood. The goal of this proposal is to identify the molecular, cellular and morphogenetic mechanisms underlying BPA-driven altered mammogenesis that predisposes to neoplastic transformation. To achieve this goal, we will use innovative tools such as a fetal mammary gland explant culture model that allows testing for direct effects of hormones and real-time observation of organogenesis. The Specific Aims of this proposal are to test three hypotheses, namely, 1: that the direct effect BPA on mammary gland development is mediated by ER1 and/or 2. 2: that BPA causes altered ductal morphogenesis i) by altering the composition and physical properties of the ECM and ii) by inducing adipogenesis. 3: that the different mammary gland phenotypes resulting from gestational and gestational plus lactational BPA exposure are due to alterations at the hypothalamic level.

描述（由申请人提供）：在人类暴露范围内以剂量的剂量暴露于双足A（BPA）会导致动物的一系列不良反应。已知这些结果也存在于人类人群中，其发生的增加与大量使用BPA和其他内分泌破坏了消费品中的化学物质。 BPA的主要激素活性是雌激素模仿。在包括胎儿发育时期在内的妇女一生中接触雌激素，被认为是乳腺癌的主要危险因素。在暴露期间，对BPA的发育暴露改变了啮齿动物的乳腺形态发生，并导致了成年后出现的肿瘤前和肿瘤病变的发展。该提案的目的是确定BPA驱动的基于BPA驱动的分子，细胞和形态发生机制改变了倾向于肿瘤转化的乳房发生。为了实现这一目标，我们将使用创新的工具，例如胎儿乳腺外植体培养模型，该模型允许测试激素的直接影响和对器官发生的实时观察。该提案的具体目的是检验三个假设，即1：直接效应BPA对乳腺发育的直接效应是由ER1和/或2。2：2：2：bpa介导的，BPA通过诱导ECM和II的组成和物理性质而改变导管形态发生i），通过诱导ECM和II）。 3：由妊娠和妊娠乳腺BPA暴露引起的不同乳腺表型是由于下丘脑水平的改变。