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）是妇女死亡的主要原因；全球发病率继续上升。遗传易感性占BCa风险的不到15%，而主要的病因因素是与环境暴露和生活方式选择有关的因素。从低风险国家移民到美国的人在一代人的时间内患BCa的风险更高。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。后者的发现表明BCa是胎儿起源的。在美国，高脂肪的饮食可能是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，也是一个可疑因素。暴露于双酚a的大鼠比未暴露的大鼠更容易受到双酚a诱导的双酚a的影响。虽然双酚a和高脂肪饮食都被单独研究过，但两者一起服用是否有协同作用还没有研究。更重要的是，表观遗传学作为一种已知的环境相互作用机制，尚未在BCa发育起源的背景下进行研究。研究人员最近发现，大鼠产前暴露于高脂肪饮食（39%的千卡）比暴露于参考饮食（16%的千卡）的对照组表现出更高的dba诱导的BCa敏感性。高脂肪饮食还诱导上皮细胞增殖显著增加，并通过全球转录组分析鉴定出独特的增殖基因特征。利用无偏倚的甲基组分析技术，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基因表达的表观遗传重编程。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期，这种相互作用会重新编程乳腺甲基组，导致基因表达异常，成年后BCa风险增加。为了验证这一假设，并通过社区外展将研究结果转化为公共卫生行动，研究人员提出了三个具体的目标：目的1：表征饮食中BPA对高脂肪饮食对成年后BPA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BPA的有效发育剂量协同作用，以提高成人BCa风险，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展项目，将研究成果转化为公众意识和行动，以减轻不良生活方式选择和环境污染物对BCa风险的负担。这项研究将首次检验表观遗传学作为环境毒物相互作用下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.