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

父母高脂肪饮食与后代患胰腺癌的风险

• 批准号: 9319232
• 负责人: Sonia de Assis
• 金额: $ 15.3万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319232
• 关键词: Adult; Adult Children; Affect; Age; Age-Months; Alleles; Animals; Automobile Driving; Birth; Birth Weight; Blood Circulation; Body Weight; Cancer Etiology; Cancer Patient; Cancerous; Carcinoma in Situ; Chronic Disease; Clinic; Clinical; Clinical Trials; Conceptions; Consumption; DNA Methylation; DNA Modification Methylases; Detection; Development; Diabetes Mellitus; Diet; Dietary Factors; Dietary Fats; Disease; Early Diagnosis; Environment; Epidemiology; Epigenetic Process; Etiology; Exposure to; Fathers; Fatty acid glycerol esters; Female; Functional disorder; Germ Lines; Goals; High Fat Diet; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Individual; Knowledge; Lead; Lesion; Life; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mammals; Measures; Methylation; Methyltransferase; MicroRNAs; Monitor; Mothers; Mus; Nutritional; Obesity; Pancreas; Pancreatic Ductal Carcinoma; Parents; Pathogenesis; Pathologist; Pattern; Phenotype; Pregnancy; Premalignant; Prevention; Preventive; Proxy; Public Health; Recommendation; Reporting; Research Design; Risk; Risk Factors; Rodent Model; ST13 gene; Survival Rate; Testing; Therapeutic Intervention; Tissues; Tumor Suppressor Genes; Weaning; cancer prevention; cancer risk; disorder risk; effective therapy; epigenetic drug; experimental study; fetal; fetal programming; genome wide methylation; human disease; in utero; male; miRNA expression profiling; modifiable risk; mouse model; nutrition; offspring; overexpression; pancreas development; pancreatic neoplasm; patient subsets; postnatal; pregnant; prenatal; prenatal exposure; public health relevance; pup; virtual

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.

描述（由申请人提供）：已经提出，包括癌症在内的成人生活中某些慢性疾病的风险受到早期发育作用的暴露的影响。流行病学和动物研究表明，较高的出生体重A替代性属于子宫内营养环境 - 与人类癌症风险的总体增加相关，包括胃肠道轨道的癌症，例如胰腺癌。使用啮齿动物模型，我们已经表明，在暴露后很长一段时间内，成人后代的产前暴露会增加成人后代的出生体重和癌症风险。其他人则表明，在受孕之前和怀孕期间，父母的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人后代的癌症表型有关的提议的机制之一是表观遗传重编程。我们已经表明，父母对高脂饮食的消费在后代的胰腺中的正常miRNA表达曲线重新编程，包括显示在胰腺癌中改变的miRNA。目的/假设：流行病学和动物研究证明了祖先/祖先/产前饮食暴露与疾病风险之间的关联。该提议的目的是调查父母在受孕之前（父亲）和怀孕期间（母亲）在肥胖饮食（OID）的消费是否会表现出后代后代的胰腺并增加胰腺癌的风险。我们假设，父母在受孕（父亲）和怀孕期间（母亲）的父母消费将导致后代胰腺的表观遗传重编程（DNA甲基化和miRNA表达），并增加其胰腺癌的风险。具体目标：目标1：确定母亲在怀孕期间对OID的消费是否与成年后代的胰腺癌风险增加有关。 AIM 2：确定父亲在受孕之前是否对OID的消费是否与成年后代的胰腺癌风险增加有关。目标3：目标3：确定父母的OID消耗是否导致其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：我们的实验将使用P48CRE/+/LSL-KRASG12D/+小鼠模型。在实验1中，在怀孕的程度（21天）中，将分别喂食含有17％（对照）或58％能量的AIN93G饮食，分别含有17％（对照）或58％的能量（肥胖引起肥胖症）。在实验2中，雄性小鼠将获得断奶（3周龄）直至性成熟度（8周龄）的对照或OID饮食。此时，所有雄性小鼠都将改用节食饮食，并与雌性小鼠一起安装。实验2中的怀孕大坝将在怀孕的程度（21天）和分娩后喂食对照饮食。两种实验中出生的幼崽将在产后第21天断奶，并在实验期间给予AIN93G控制饮食。后代的胰腺组织将在产后日（PND）50，然后在12个月大时再次收集。将评估从p48cre/+/+/+/lsl-krasg12d/+ 12个月收集的小鼠的胰腺组织，以确定病理学家的胰腺癌（Panin）和胰腺导管癌（PDAC）的病理学家，以确定父母的OID OID Offortumption对partic turotic pareat pareat partic parting的影响。缺少P48CRE或LSL-KRASG12D等位基因的同窝仔用作对照。在PND50上收集的胰腺组织将用于microRNA分析和全球甲基化分析，以确定父母OID消耗对后代胰腺表观遗传编程的影响。

项目成果

Investigation of Paternal Programming of Breast Cancer Risk in Female Offspring in Rodent Models.

啮齿动物模型中雌性后代乳腺癌风险的父系编程调查。

• DOI: 10.1007/978-1-4939-7614-0_11
• 发表时间: 2018
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Fontelles,CamileCastilho;daCruz,RaquelSantana;Hilakivi-Clarke,Leena;deAssis,Sonia;Ong,ThomasPrates
• 通讯作者: Ong,ThomasPrates