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

描述（由申请人提供）：乳腺癌（BCa）是女性死亡的主要原因;全球发病率持续上升。遗传易感性占BCa风险的不到15%，而主要病因因素与环境暴露和生活方式选择有关。 来自低风险国家的美国移民在一代人内发展出更高的BCa风险。此外，第二代的风险取决于一个人的母亲是来自祖国还是美国。后一个发现表明BCa是胎儿来源的。在美国，高脂肪饮食可能是BCa的主要风险因素。啮齿动物研究表明，脂肪的类型和特定的关键暴露窗口是这种联系的关键决定因素。环境雌激素，双酚A（BPA），在美国人群中无处不在，也是一个怀疑。出生前/围产期暴露于BPA的大鼠比未暴露的大鼠更容易受到DMBA诱导的BCa的影响。 虽然BPA和高脂饮食已分别进行了研究，但这两种饮食一起使用是否具有协同作用尚未研究。更重要的是，表观遗传学，一个已知的机制，基因与环境的相互作用，还没有被研究的背景下，发育起源的BCa。 研究人员最近发现，出生前暴露于高脂肪饮食（39%千卡）的大鼠比暴露于参考饮食（16%千卡）的对照组表现出更高的DMBA诱导的BCa敏感性。高脂饮食还诱导上皮细胞增殖的显著增加，沿着通过全局转录组谱鉴定的独特增殖基因签名。使用无偏见的甲基化组分析技术，研究人员还生成了初步数据，支持产前暴露于高脂肪饮食后成年乳腺中基因表达的表观遗传重编程。在这里，他们提出妊娠期是膳食脂肪酸-BPA相互作用的关键发育窗口，重新编程乳腺甲基化，导致基因表达异常和成年后BCa风险增加。提出了三个具体的施舍来检验这一假设，并通过社区外展将发现转化为公共卫生行动：目的1：描述膳食BPA对高脂肪饮食对晚年BCa风险的发育影响的剂量反应;目的2：描述（a）脂肪类型是否与有效发育剂量的BPA协同作用，提高成人BCa风险，以及（B）是否存在甲基化，沿着异常乳腺上皮细胞增殖基因特征，反映了合并暴露;目标3：通过与粉红丝带女孩合作的外展计划，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。这项研究将是第一个研究表观遗传学作为一种机制的生活方式选择的环境毒物的相互作用。

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.