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增加暂时与内分泌干扰物暴露量的增加有关。双酚A（BPA）是塑料和树脂的一种成分，它会渗入食品和饮料产品中，并在正常人血清、羊水和胎儿中检测到。BPA在体外和体内都具有雌激素特性，对啮齿动物进行产前或围产期治疗会促进成年人乳腺腺泡的不适当发育和增殖。虽然这种乳腺反应预示着乳腺癌的发生，但没有研究报告直接评估BPA暴露后乳腺癌易感性是否确实改变。我们的中心假设是，产前暴露于双酚A将增加乳腺肿瘤的易感性在成年小鼠。我们预测，这种易感性的增加将是由于腺体内和激素环境中的联合发育变化。在乳腺原基形成期间，改变的雌激素环境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。除了改变终末器官的敏感性外，我们预计BPA暴露女性的内分泌环境会发生中心变化。我们预计，这些因素合作，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。我们将使用化学致癌物范例直接评估产前暴露于BPA的乳腺的肿瘤易感性。我们还将确定BPA引起的慢性增生是否是由于内在乳腺上皮变化、激素改变或两者兼而有之。最后，我们将描述乳腺转录组中整合这些输入以形成增生腺体的变化。这将为未来的工作奠定基础，研究产前BPA暴露改变这些基因/途径表达的机制，以及确定这些基因的明显操纵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.