BPA as a Developmental Carcinogen

BPA 作为一种发育致癌物

• 批准号: 8230305
• 负责人: ANA SOTO
• 金额: $ 18.37万
• 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/8230305
• 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; Research Personnel; 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

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 (EDCs) 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. The investigators 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. The investigators 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 the investigator's laboratory and that of Dr. S. Fenton (NIEHS). The investigators will compare subjective scoring methods with morphometric ones, and determine which are the features that best predict neoplastic outcomes. The investigators 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. The investigators 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.

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口中，并且其发生的增加与消费品中BPA和其他内分泌干扰化学物质（EDC）的大量使用相吻合。 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。研究人员发现，在暴露期间，啮齿动物中乳腺的形态发生改变了与环境相关的剂量的发育暴露，并导致了杜鹃花前和肿瘤病变的发展。这些结果证明了将乳腺相关的端点添加到大型且控制良好的GLP NTP-FDA研究中的合理性。研究人员建议追求以下特定目的：1）检验以下假设：pND21上形态图评估的柱前乳腺形态学是表现在成年期间表现出的病理结果的极好预测指标。该目标基于研究人员的实验室和S. Fenton博士（NIEHS）独立获得的数据。研究人员将将主观评分方法与形态计量学的方法进行比较，并确定哪些特征是最能预测肿瘤结果的特征。研究人员将评估暴露于PND21的整个动物。 2）检验以下假设：乳腺基质中基因表达的DNA甲基化谱和pND21上皮的基因表达的改变是表现在成年期间表现出的病理结果的预测指标。 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。研究人员将评估导管内增生，原位癌和微观肿瘤的发展，以及从I）GD6暴露于i）GD6的动物的明显肿瘤的出现，直到PND 21和ii）从GD6持续到牺牲。 这些目标的实现将确定检验以下假设：围产期BPA暴露使个体易患乳腺癌并揭示剂量反应模式。此外，它将确定候选分子标记和形态学体征是肿瘤结果的预测指标。这些知识对于BPA的毒理学评估至关重要。该项目的成功表明，其中一些乳腺末端指向化学物质的毒理学评估。