Mammary cancer suceptibility following in utero exposure to bisphenol A

描述(由申请人提供)：发达国家乳腺癌发病率的上升暂时与内分泌干扰剂的暴露增加有关。双酚A(BPA)是塑料和树脂中的一种成分，可渗入食品和饮料产品中，已在正常的人血清、羊水和胎儿中检测到。BPA在体外和体内都具有雌激素性质，对啮齿类动物的产前或围产期治疗会促进成年大鼠乳腺泡的不适当发育和增殖。虽然这种乳腺反应预示着发生乳腺癌的倾向，但还没有直接评估双酚A暴露后乳腺癌易感性是否真的改变的研究报道。我们的中心假设是，产前暴露于双酚A会增加成年小鼠乳腺肿瘤的易感性。我们预测，这种易感性的增加将是由于腺体内和荷尔蒙环境中的联合发育变化。在乳腺原纤维的形成过程中，雌激素环境的改变可能传递一种不可逆转的适应性反应，使乳腺本质上更容易形成增生，这是一种癌前状态。除了改变终末器官敏感度外，我们预计接触双酚A的女性内分泌环境也会发生中心变化。我们预计，这些因素协同作用，创造了一个改变的转录组，使乳腺易于在以后的生活中发生致癌事件。我们将使用化学致癌物范例直接评估产前暴露于双酚A的乳腺的肿瘤敏感性。我们还将确定双酚A诱导的慢性增生是由于固有的乳腺上皮变化，还是荷尔蒙变化，还是两者兼而有之。最后，我们将描述乳腺转录组的变化，这些变化整合了这些输入，形成了一个增生性腺体。这将为未来的工作奠定基础，检查这些基因/途径的表达因产前暴露于BPA而改变的机制，以及确定这些基因的公开操作是否会改变乳腺癌风险。

DESCRIPTION (provided by applicant): The increasing rates of breast cancer occurring in developed countries have been tentatively linked to elevated exposure to endocrine disrupting agents. One such agent, bisphenol A (BPA), is a component of plastics and resins that leaches into food and beverage products and has been detected in normal human serum, amniotic fluid, and fetuses. BPA has estrogenic properties both in vitro and in vivo and pre- or perinatal treatment of rodents promotes inappropriate development and proliferation of mammary gland alveoli in adults. While this mammary gland response portends a predilection for development of mammary cancer, no studies have been reported that directly assess whether mammary cancer susceptibility is indeed altered following BPA exposure. Our central hypothesis is that prenatal exposure to bisphenol A will increase mammary gland tumor susceptibility in adult mice. We predict that this increase in susceptibility will be due to combined developmental changes both within the gland and in the hormonal milieu. During formation of the mammary anlagen, an altered estrogenic environment may convey an irreversible adaptive response, making the gland intrinsically more susceptible to the formation of hyperplasia, a preneoplastic state. In addition to altering end organ sensitivity, we expect a central change in the endocrine environment of BPA exposed females. We anticipate that these factors collaborate, creating an altered transcriptome that predisposes the mammary gland to carcinogenic events later in life. We will directly assess the tumor susceptibility of mammary glands that prenatally exposed to BPA using a chemical carcinogen paradigm. We also will determine if chronic hyperplasia induced by BPA is due to intrinsic mammary epithelial changes, hormonal alterations, or both. Lastly, we will characterize changes in the mammary gland transcriptome that integrate these inputs to form a hyperplastic gland. This will build a foundation for future work examining mechanisms by which expression of these genes/pathways is changed by prenatal BPA exposure as well as determining if overt manipulation of these genes alters breast cancer risk.