BPA as a Developmental Carcinogen

描述（由申请方提供）：在人类暴露范围内的剂量下，发育暴露于双酚A（BPA）会导致动物产生一系列复杂的不良反应。这些结果也存在于人群中，其发生率的上升与消费品中大量使用BPA和其他内分泌干扰化学品（EDCs）相吻合。BPA的主要激素活性是作为雌激素模拟物。 在妇女的一生中，包括胎儿发育期间，暴露于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，发育暴露于环境相关剂量的BPA改变了啮齿动物的乳腺形态发生，并导致在成年期出现肿瘤前病变和肿瘤病变。这些结果证明了在大型和良好对照的GLP NTP-FDA研究中增加乳腺相关终点的合理性。研究者建议追求以下特定目的：1）检验以下假设：在PND 21时通过形态测定法评估的青春期前乳腺形态是成年期表现的病理结果的良好预测因子。这一目标是基于研究者实验室和S. 芬顿（NIEHS）。研究人员将比较主观评分方法与形态测量方法，并确定哪些特征最能预测肿瘤结局。研究者将评估暴露至PND 21的整批动物。2)检验PND 21时乳腺基质和上皮中DNA甲基化谱和伴随的基因表达改变是成年期表现的病理结果的预测因子的假设。3)检验围产期暴露于BPA诱导肿瘤前病变和肿瘤病变发展的假设。研究者将评估从i）GD 6至PND 21和ii）从GD 6至处死连续暴露的动物中导管内增生、原位癌和显微镜下肿瘤的发展以及可触及肿瘤的外观。 这些目标的实现将明确测试的假设，围产期BPA暴露易患乳腺癌的个人，并揭示剂量反应模式。此外，它将确定候选分子标志物和形态学体征作为肿瘤结局的预测因子。这些知识对于BPA的毒理学评价至关重要。这一项目的成功将表明在化学品的毒理学评估中增加其中一些乳腺终点。

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.