BPA as a Developmental Carcinogen

BPA 作为一种发育致癌物

• 批准号: 8686845
• 负责人: ANA SOTO
• 金额: $ 17.9万
• 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/8686845
• 关键词: Address; Adult; Adverse effects; Age; American; Animals; Apoptosis; Appearance; Barker Hypothesis; Biochemical; Breast Cancer Risk Factor; Breast Carcinogenesis; 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; 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.

在人类暴露范围内，发育量暴露于双酚A（BPA）导致A 动物的复杂阵列不良反应。这些结果也存在于人类中 种群及其发生的兴起与大量使用BPA和其他内分泌相吻合 破坏消费品中的化学物质。 BPA的主要激素活性是雌激素模仿。 在整个女人的生活中，包括胎儿发育时期，接触雌激素，被认为是 乳腺癌的主要危险因素。我们发现发育与环境相关剂量的暴露 BPA在暴露期间改变了啮齿动物的乳腺形态发生，并导致 成年后出现的肿瘤前和肿瘤病变的发展。这些结果证明添加合理 乳腺相关的终点指向大型且控制良好的GLP NTP-FDA研究。我们建议 追求以下特定目的：1）检验假设前乳腺形态的假设 在PND21上通过形态学评估是表现出的病理结果的出色预测指标 在成年期。该目标基于在我们的实验室和S.博士的数据中独立获得的数据。 芬顿（Niehs）。我们将将主观评分方法与形态计量学的方法进行比较，并确定哪种 是最能预测肿瘤结果的功能。我们将评估暴露的整个动物 直到PND21。 2）测试DNA甲基化谱和基因伴随改变的假设 PND21的乳腺基质和上皮中的表达是病理结局的预测指标 在成年期间表现出来。 3）检验以下假设：围产期暴露于BPA会诱导 肿瘤前和肿瘤病变的发展。我们将评估导管内的发展 增生，癌原位和微观肿瘤以及动物明显肿瘤的出现 从i）GD6暴露到PND 21和II）从GD6持续牺牲。 这些目标的实现将确定检验围产期BPA暴露易感性的假设 患有乳腺癌的个体并揭示了剂量反应模式。此外，它将确定候选人 分子标记和形态迹象是肿瘤结局的预测指标。这些知识至关重要 用于BPA的毒理学评估。该项目的成功表明增加了一些 这些乳腺末端指向化学物质的毒理学评估。