BPA as a Developmental Carcinogen

描述（由申请人提供）：在人类暴露剂量范围内的双酚a （BPA）发育暴露会在动物中引起一系列复杂的不良反应。众所周知，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双酚a和其他内分泌干扰化学物质（EDCs）相吻合。BPA的主要激素活性是雌激素的模拟物。女性一生中，包括胎儿发育期间，都接触到雌激素，这被认为是患乳腺癌的主要风险因素。研究人员发现，发育过程中暴露于与环境相关剂量的双酚a会改变啮齿动物的乳腺形态发生，并导致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控制良好的GLP NTP- FDA研究中加入乳腺相关终点是合理的。研究人员提出以下具体目的：1)验证PND21形态计量学评估的青春期前乳腺形态是成年期病理结果的良好预测因子的假设。这一目标是基于研究者实验室和S. Fenton博士（NIEHS）独立获得的数据。研究人员将比较主观评分方法和形态学评分方法，并确定哪种特征最能预测肿瘤的预后。调查人员将对暴露在PND21之前的所有动物进行评估。2)验证PND21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病理结果的预测因子的假设。3)验证围产期BPA暴露诱导肿瘤前病变和肿瘤病变发展的假说。研究人员将评估1)GD6暴露至PND 21和2)从GD6持续暴露至死亡的动物的导管内增生、原位癌和显微肿瘤的发展以及可触及肿瘤的出现。这些目标的实现将最终验证围产期BPA暴露使个体易患乳腺癌的假设，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标志作为肿瘤预后的预测因子。这些知识对于BPA的毒理学评估至关重要。这个项目的成功将意味着在化学品的毒理学评估中增加一些乳腺终点。

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.