Mammary cancer suceptibility following in utero exposure to bisphenol A

发达国家乳腺癌发病率的上升暂时被认为与乳腺癌发病率升高有关。 暴露在内分泌干扰剂中。其中一种试剂双酚A(BPA)是塑料的一种成分， 渗入食品和饮料产品中的树脂，并在正常人体血清中检测到， 羊水和胎儿。双酚A在体外和体内以及产前或围产期都具有雌激素性质。 治疗啮齿动物促进小鼠乳腺腺泡发育不良和增殖 成年人。虽然这种乳腺反应预示着乳腺癌的发展倾向， 目前还没有直接评估乳腺癌易感性是否确实发生改变的研究报道。 在接触双酚A之后。我们的中心假设是，产前接触双酚A会增加 成年小鼠乳腺肿瘤易感性的研究。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的综合发育变化。在形成过程中， 乳腺组织，雌激素环境的改变可能传递不可逆的适应性反应， 使腺体本质上更容易形成增生，一种癌前状态。在……里面 除了改变终末器官的敏感性外，我们预计BPA的内分泌环境也会发生中心变化 裸露的雌性。我们预计这些因素协同作用，创造了一个改变的转录组， 使乳腺在以后的生活中容易发生致癌事件。我们将直接评估肿瘤 使用化学致癌物范例研究产前暴露于双酚A的乳腺的易感性。我们 也将确定双酚A诱导的慢性增生是否是由于固有的乳腺上皮变化， 荷尔蒙变化，或者两者兼而有之。最后，我们将描述乳腺转录组的变化 将这些输入整合起来，形成一个增生性腺体。这将为今后的工作审查奠定基础 这些基因/途径的表达通过产前暴露和双酚A改变的机制 确定这些基因的公开操作是否会改变乳腺癌的风险。

The increasing rates of breast cancer occuring in developed countries has 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.