BPA as a Developmental Carcinogen

在人类暴露范围内的剂量下，发育暴露于双酚A（BPA）会导致 对动物的一系列复杂的不利影响。这些结果也已知存在于人类中， 人口和其发生率的上升与BPA和其他内分泌激素的大量使用相吻合 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。 暴露于雌激素在整个妇女的生活，包括胎儿发育期，被认为是一个 乳腺癌的主要危险因素。我们发现发育期暴露于环境相关剂量 在接触期间，BPA改变了啮齿动物乳腺的形态发生， 在成年期出现肿瘤前病变和肿瘤病变。这些结果证明， 乳腺相关终点的大型和良好对照的GLP NTP-FDA研究。我们建议 具体目的如下：1）验证青春期前乳腺形态学的假设， 在PND 21时通过形态测定法评估的是病理结果的极好预测因子， 在成年期。这一目标是基于我们实验室独立获得的数据和S. 芬顿（NIEHS）。我们将比较主观评分方法与形态测量方法，并确定 是最能预测肿瘤结果的特征。我们将评估暴露在 直到PND 21。2)为了验证DNA甲基化谱和伴随的基因改变可能是一种基因突变的假说， PND 21时乳腺间质和上皮中的表达是病理结果的预测因子 在成年期表现出来。3)为了验证围产期暴露于BPA会导致 肿瘤前病变和肿瘤病变的发展。我们将评估导管内 增生、原位癌和显微镜下肿瘤以及动物中可触及肿瘤的外观 从I）GD 6至PND 21暴露，和ii）从GD 6至处死连续暴露。 这些目标的实现将最终检验围产期BPA暴露易导致 个体对乳腺癌的影响，并揭示了剂量反应模式。此外，它还将确定候选人 分子标志物和形态学体征作为肿瘤结果的预测因子。这些知识至关重要 BPA的毒理学评估。该项目的成功将建议增加一些 这些乳腺终点指向化学品的毒理学评估。

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.