Susceptible Window of High Fat Diet/Bisphenol A Programming of Breast Cancer Risk

描述(申请人提供)：乳腺癌(BCA)是女性死亡的主要原因；全球发病率持续上升。遗传易感性在BCA风险中所占比例不到15%，而主要致病因素是与环境暴露和生活方式选择有关的因素。来自低风险国家的移民在一代人的时间内患上更高的BCA风险。此外，第二代的风险取决于一个人的母亲是本国人还是美国人。后一项发现表明BCA起源于胎儿。高脂肪饮食可能是美国BCA的主要风险因素。啮齿动物研究表明，脂肪的类型和暴露的特定关键窗口是这种联系的关键决定因素。在美国人群中普遍存在的环境雌激素双酚A(BPA)也是一个可疑因素。出生前/围产期暴露于BPA的大鼠比未暴露的大鼠更容易发生DMBA诱导的BCA。虽然双酚A和高脂肪饮食已经被单独研究，但这两种饮食一起服用是否具有协同作用还没有调查。更重要的是，表观遗传学，一种已知的基因与环境相互作用的机制，还没有在BCA的发育起源的背景下进行研究。研究人员最近发现，产前暴露于高脂肪饮食的大鼠(39%千卡)比对照组(16%千卡)表现出更高的DMBA诱导的BCA易感性。高脂饮食还诱导了上皮细胞增殖的显着增加，以及全球转录组图谱确定的独特的增殖基因特征。使用一种无偏见的甲基组图谱技术，研究人员还生成了初步数据，以支持产前暴露于高脂肪饮食后成人乳腺中基因表达的表观遗传重新编程。在这里，他们提出妊娠期是饮食脂肪酸-BPA相互作用的关键发育窗口，这种相互作用重新编程乳房甲基组，导致基因表达异常，成年后BCA风险增加。为了验证这一假说，并通过社区推广将发现转化为公共卫生行动，提出了三种具体的救济方法：目的1：描述饮食BPA对高脂肪饮食对老年BCA风险的发育影响的剂量-反应；目标2：描述(A)脂肪类型是否与BPA的有效发育剂量在增加成人BCA风险方面协同作用，以及(B)甲基组以及异常的乳腺上皮细胞增殖基因特征是否反映了联合暴露；目标3：通过与粉红丝带女孩合作的外联计划，将研究结果转化为公众意识和行动，以减少不良生活方式选择和环境污染物对BCA风险的负担。这项研究将首次考察表观遗传学作为通过环境毒物相互作用而导致的生活方式选择的机制。

DESCRIPTION (provided by applicant): Breast cancer (BCa) is the leading cause of death in women; incidence rates continue to rise globally. Genetic predisposition accounts for less than 15% of BCa risk while main etiological factors are those related to environmental exposure and lifestyle choices. Immigrants to the US from low-risk countries develop a higher BCa risk within one generation. Moreover, risk in the second generation is dependent on whether one is born to mother from homeland or US. The latter finding suggests BCa is of fetal origin. A diet high in fat is likely a major risk factor of BCa in the U.S. Rodent studies showed that the type of fat and the particular critical window of exposure are key determinants of this linkage. The environmental estrogen, Bisphenol A (BPA), found ubiquitously in US populations, is also a suspect. Rats exposed to BPA pre-/peri-natally are more susceptible to DMBA-induced BCa than their unexposed counterparts. Although both BPA and high-fat diets have been separately studied, whether the two, given together, have synergistic action has not been investigated. More importantly, epigenetics, a known mechanism underlying gene by environment interaction, has not been studied in the context of developmental origin of BCa. The investigators recently showed that rats prenatally exposed to high-fat diets (39% of kcal) exhibited a higher DMBA-induced BCa susceptibility than controls exposed to a reference diet (16% of kcal). The high-fat diets also induced marked increases in epithelial cell proliferation along with a unique proliferation gene signature identified by global transcriptome profiling. Using an unbiased methylome profiling technique, the investigators also generated preliminary data in support of epigenetic reprogramming of gene expression in adult mammary glands after prenatal exposure to high-fat diets. Here, they propose the gestational period is a critical developmental window for dietary fatty acids-BPA interaction, that reprograms the mammary methylome, resulting in aberrant gene expression and increased BCa risk in adulthood. Three specific alms are proposed to test this hypothesis and translate findings Into public health action through community outreach: Aim 1: To characterize the dose-response of dietary BPA on the developmental effects of high-fat diets on BCa risk in later-life; Aim 2: To delineate (a) if the type of fat matters in synergizing with an effective developmental dose of BPA in elevating adult BCa risk, and (b) if a methylome, along with an aberrant mammary epithelial cell proliferative gene signature, is reflective of the combined exposure; and Aim 3: To translate research findings into public awareness and action to reduce the burden of adverse lifestyle choices and environmental pollutants on BCa risk through an outreach program that partners with the Pink Ribbon Girls. This study will be the first to examine epigenetics as a mechanism underlying lifestyle choices by environmental toxicant Interaction.