BPA as a Developmental Carcinogen

发育过程中暴露于双酚A(BPA)的剂量在人类暴露范围内会导致 对动物的一系列复杂的不良影响。这些结果也已知在人类身上也存在 双酚A和其他内分泌物质的大量使用及其发病率的上升恰好发生在 破坏消费品中的化学物质。双酚A的主要激素活性是作为雌激素的模拟物。 在妇女的一生中，包括胎儿发育期，暴露于雌激素被认为是一种 乳腺癌的主要危险因素。我们发现，发育过程中暴露于与环境相关的剂量 在暴露期间，BPA改变了啮齿动物的乳腺形态发生，并导致 成年期出现的癌前病变和肿瘤病变的发展。这些结果证明有必要添加 与乳腺相关的终点是大型且控制良好的GLP NTP-FDA研究。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 PND21的形态计量学评估是一个很好的预测病理结果的指标 在成年的时候。这一目标是基于我们实验室和S博士独立获得的数据。 芬顿(NIEHS)。我们将比较主观计分方法和形态计分方法，并确定哪种方法 是最能预测肿瘤结果的特征。我们将评估整批暴露的动物 直到PND21。2)检验DNA甲基化图谱和伴随的基因改变的假设 PND21在乳腺间质和上皮中的表达是预测病理结果的指标 这一点在成年后表现出来。3)检验围产期暴露于双酚A会导致 肿瘤前病变和肿瘤病变的发展。我们将评估导管内的发育情况 动物的增生、原位癌和显微肿瘤以及可触及的肿瘤的出现 暴露于I)GD6至PND 21和II)从GD6持续至处死。 这些目标的实现将最终检验围产期接触双酚A易患上双酚A的假设 并揭示个体对乳腺癌的剂量-反应模式。此外，它还将确定候选人 分子标记和形态标志作为肿瘤预后的预测因子。这方面的知识至关重要。 用于双酚A的毒理学评估。这个项目的成功将意味着增加一些 这些乳腺末端指向对化学物质的毒理学评估。

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.