Parental Exposure to High Fats Diets and Risk of Pancreatic Cancer in the Offspri

描述（由申请人提供）：有人提出，成人生活中某些慢性疾病（包括癌症）的风险受到早期发育中作用的暴露的影响。流行病学和动物研究表明，高出生体重子宫内营养环境的替代指标与人类癌症风险的总体增加有关，包括胃肠道癌症，如胰腺癌。使用啮齿动物模型，我们已经表明，产前暴露于高脂肪饮食会增加出生体重，并在暴露后很长一段时间内增加成年后代的癌症风险。其他研究表明，在怀孕前和怀孕期间，父母营养和体重不足会导致后代的胰腺功能障碍。祖先/产前饮食暴露可能与成年后代的癌症表型相关的拟议机制之一是表观遗传重编程。我们已经证明，父母食用高脂肪饮食会重新编程后代胰腺中的正常miRNA表达谱，包括在胰腺癌中被改变的miRNA。目的/假设：流行病学和动物研究表明，祖先/产前饮食接触与疾病风险（包括癌症）之间存在关联。这项提案的目的是调查父母在怀孕前（父亲）和怀孕期间（母亲）是否食用肥胖诱导饮食（肥胖饮食）会表观遗传地重新编程后代的胰腺并增加他们患胰腺癌的风险。我们假设，父母在怀孕前（父亲）和怀孕期间（母亲）食用甜菜碱会导致后代胰腺的表观遗传重编程（DNA甲基化和miRNA表达），并增加他们患胰腺癌的风险。具体目标：目标1：确定母亲在怀孕期间摄入的叶酸是否与其后代成年后胰腺癌风险增加有关。目标二：确定父亲在怀孕前食用酒精是否与其后代成年后胰腺癌风险增加有关。目标3：目标3：确定父母摄入的β-淀粉样蛋白是否会导致后代正常胰腺组织中的表观遗传重编程（DNA甲基化和miRNA表达）。研究设计：胰腺癌的p48 Cre/+ /LSL-KrasG 12 D/+小鼠模型将用于我们的实验。在实验1中，妊娠雌性动物将在妊娠期（21天）分别喂食含有17%（对照）或58%脂肪能量（肥胖诱导饮食，EAD）的AIN 93 G饮食。在实验2中，从断奶（3周龄）至性成熟（8周龄），雄性小鼠将喂食对照或非对照饲料;此时，所有雄性小鼠将转换为对照饲料，并与雌性小鼠一起饲养。实验2中的妊娠母鼠将在妊娠期间（21天）和分娩后饲喂对照饲料。在两个实验中出生的幼仔将在出生后第21天断奶，并在实验期间喂食AIN 93 G对照饮食。将在出生后第50天（PND）收集后代的胰腺组织，并在12月龄时再次收集。由病理学家评价在12个月时收集的来自p48 Cre/+ /LSL-KrasG 12 D/+小鼠的胰腺组织的胰腺原位癌（PanIN）和胰腺导管癌（PDAC），以确定亲代胰腺消耗对后代胰腺肿瘤发展的影响。将缺乏p48 Cre或LSL-KrasG 12 D等位基因的同窝仔用作对照。在PND 50收集的胰腺组织将用于microRNA谱分析和全局甲基化分析，以确定亲本胰腺消耗对后代胰腺的表观遗传编程的影响。

DESCRIPTION (provided by applicant): It has been proposed that the risk of some chronic diseases in adult life, including cancer, is influenced by exposures acting in early development. Epidemiologic as well as animals studies show that high birth weight-a proxy measure of the in utero nutritional environment-is associated with an overall increase in cancer risk in humans, including cancers of the gastrointestinal track such as pancreatic cancer. Using rodent models, we have shown that prenatal exposure to a high-fat diet increases birth weight and cancer risk in the adult offspring long after the exposure. Others have shown that inadequate parental nutrition and body weight before conception and during pregnancy leads to pancreatic dysfunction in the offspring. One of the proposed mechanisms by which ancestral/prenatal dietary exposures could be linked to cancer phenotypes in the adult offspring is epigenetic reprogramming. We have shown that show that parental consumption of high fat diet reprograms the normal miRNA expression profile in the offspring's pancreas, including miRNAs shown to be altered in pancreatic cancers. Objective/hypothesis: An association between ancestral/prenatal dietary exposures and disease risk, including cancer, been demonstrated by epidemiologic and animal studies. The goal of this proposal is to investigate whether parental consumption of obesity-inducing diet (OID) before conception (fathers) and during pregnancy (mothers) will epigenetically reprogram the offspring's pancreas and increase their risk of pancreatic cancer. We postulate that parental consumption of OID before conception (fathers) and during pregnancy (mothers) will lead to epigenetic reprogramming (DNA methylation and miRNA expression) of the offspring's pancreas and increase their risk of pancreatic cancer. Specific Aims: Aim 1: Determine whether mothers' consumption of OID during pregnancy is associated with increased pancreatic cancer risk in their offspring in adulthood. Aim 2: Determine whether consumption of OID by fathers before conception is associated with increased pancreatic cancer risk in their offspring in adulthood. Aim 3: Aim 3: Determine whether parental consumption of OID leads to epigenetic reprogramming (DNA methylation and miRNA expression) in normal pancreas tissue of their offspring. Study Design: The p48Cre/+ /LSL-KrasG12D/+ mouse model of pancreatic cancer will be used in our experiments. In experiment 1, pregnant females will be fed AIN93G diets containing either 17% (control) or 58% energy from fat (Obesity-Inducing-Diet, OID), respectively, for the extent of pregnancy (21 days). In experiment 2, male mice will be fed a control or OID diet from weaning (3 weeks of age) until sexual maturity (8 weeks of age); at this point all male mice will be switched to contro diet and housed together with female mice. Pregnant dams in experiment 2 will be fed the control diet for the extent of pregnancy (21 days) and after giving birth. Pups born in both experiments will be weaned on postnatal day 21 and fed the AIN93G control diet for the duration of the experiment. Offspring's pancreatic tissues will be collected on post-natal day (PND) 50 and again at 12 months of age. Pancreatic tissue from the p48Cre/+ /LSL-KrasG12D/+ of mice collected at 12 months will be evaluated for pancreatic in situ carcinoma (PanIN) and Pancreatic ductal carcinomas (PDAC) by a pathologist to determine the effects of parental OID consumption on offspring's pancreatic tumor development. Littermates lacking either the p48Cre or LSL-KrasG12D allele will be used as controls. Pancreatic tissue collected on PND50 will be used to for microRNA profiling and global methylation analysis to determine the effects of parental OID consumption on epigenetic programming of the offspring's pancreas.