BPA as a Developmental Carcinogen

BPA 作为一种发育致癌物

• 批准号: 8334567
• 负责人: ANA SOTO
• 金额: $ 32.91万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334567
• 关键词: Address; Adult; Adverse effects; Age; American; Animals; Apoptosis; Appearance; Barker Hypothesis; Biochemical; Breast; Breast Cancer Risk Factor; Candidate Disease Gene; Carcinogens; Carcinoma in Situ; Cell Proliferation; Chemicals; Collaborations; Complex; DNA Methylation; Data; Development; Dose; Duct (organ) structure; Endocrine Disruptors; Endocrine disruption; Environment; Epithelium; Estrogens; Evaluation; Exposure to; Fetal Development; Gene Expression; Gene Expression Alteration; Gene Expression Profile; Health Policy; Hormonal; Human; Hyperplasia; Inbred WF Rats; Incidence; Individual; Instruction; Intraductal Hyperplasia; Knowledge; Laboratories; Lesion; Life; Link; Longevity; Mammary Neoplasms; Mammary gland; Mediating; Methods; Methylation; Microscopic; Molecular; Morphology; Mus; National Institute of Environmental Health Sciences; Neoplastic Cell Transformation; Outcome; Palpable; Pattern; Perinatal; Perinatal Exposure; Play; Population; Predisposition; Proteins; Puberty; Public Health; Publications; Rattus; Risk; Rodent; Role; Scoring Method; Sprague-Dawley Rats; Testing; Tissues; Wistar Rats; Woman; base; bisphenol A; carcinogenesis; dimethylbenzanthracene; exposed human population; genome-wide; malignant breast neoplasm; mammary gland development; mast cell; molecular marker; morphometry; neoplastic; prenatal exposure; pup; response; success; tumor; xenoestrogen

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. We found that developmental exposure to environmentally relevant doses of 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. These results justify adding mammary gland related end points to the large and well-controlled GLP NTP- FDA study. We propose to pursue the following Specific Aims: 1) To test the hypothesis that pre-pubertal mammary gland morphology assessed by morphometries at PND21 is an excellent predictor of pathological outcomes which manifest during adulthood. This aim is based on data obtained independently in our laboratory and that of Dr. S. Fenton (NIEHS). We will compare subjective scoring methods with morphometric ones, and determine which are the features that best predict neoplastic outcomes. We will assess whole mounts of animals exposed until PND21. 2) To test the hypothesis that DNA methylation profiles and concomitant alterations of gene expression in the mammary gland stroma and epithelium at PND21 are predictors of pathological outcomes that manifest during adulthood. 3) To test the hypothesis that perinatal exposure to BPA induces the development of pre-neoplastic and neoplastic lesions. We will assess the development of intraductal hyperplasias, carcinomas in situ and microscopic tumors and the appearance of palpable tumors In animals exposed from I) GD6 until PND 21 and ii) continuously from GD6 to sacrifice. The realization of these Aims will definitively test the hypothesis that perinatal BPA exposure predisposes individuals to mammary cancer and reveal the dose-response pattern. Additionally it will identify candidate molecular markers and morphological signs as predictors of neoplastic outcomes. This knowledge is crucial for the toxicological evaluation of BPA. The success of this project would suggest the addition of some of these mammary gland end points to the toxicological assessment of chemicals.

发育过程中接触双酚 A (BPA) 的剂量在人体接触范围内会导致 对动物产生一系列复杂的不利影响。已知这些结果也存在于人类中 人口及其发生率的上升与 BPA 和其他内分泌药物的大量使用同时发生 破坏消费品中的化学物质。 BPA 的主要激素活性是作为雌激素模拟物。 女性一生（包括胎儿发育期间）接触雌激素被认为是 乳腺癌的主要危险因素。我们发现，与环境相关的剂量的发育暴露 BPA 在接触期间改变了啮齿动物的乳腺形态发生，并导致 成年期出现的肿瘤前期和肿瘤病变的发展。这些结果证明添加 大型且控制良好的 GLP NTP-FDA 研究的乳腺相关终点。我们建议 追求以下具体目标： 1) 检验青春期前乳腺形态的假设 通过 PND21 的形态测量评估是病理结果的极好预测因子，这表明 成年期间。这一目标是基于我们实验室和 S. 博士的实验室独立获得的数据。 芬顿（NIEHS）。我们将比较主观评分方法与形态测量方法，并确定哪种方法 是最能预测肿瘤结果的特征。我们将评估暴露在外的全部动物 直到 PND21。 2) 检验 DNA 甲基化谱和伴随的基因改变的假设 PND21 时乳腺基质和上皮中的表达是病理结果的预测因子 在成年期间表现出来。 3) 检验围产期接触 BPA 会导致 肿瘤前期和肿瘤病变的发展。我们将评估导管内的发展 动物中的增生、原位癌和显微肿瘤以及可触及肿瘤的出现 从 I) GD6 直至 PND 21 暴露，以及 ii) 从 GD6 持续暴露至处死。 这些目标的实现将明确检验围产期 BPA 暴露易诱发这一假设 个体对乳腺癌的影响并揭示剂量反应模式。此外，它将确定候选人 分子标记和形态学标志作为肿瘤结果的预测因子。这些知识至关重要 用于BPA的毒理学评价。该项目的成功建议增加一些 这些乳腺终点指向化学品的毒理学评估。