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）：有人提出，成人生活中一些慢性疾病（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，包括胰腺癌等胃肠道癌症。使用啮齿动物模型，我们发现，产前接触高脂肪饮食会增加成年后代的出生体重和患癌症的风险。其他研究表明，受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/产前饮食暴露与成年后代癌症表型相关的拟议机制之一是表观遗传重编程。我们的研究表明，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，包括在胰腺癌中发生改变的 miRNA。目的/假设：流行病学和动物研究已证明祖先/产前饮食暴露与疾病风险（包括癌症）之间存在关联。该提案的目的是调查父母在受孕前（父亲）和怀孕期间（母亲）食用肥胖诱导饮食（OID）是否会在表观遗传上重新编程后代的胰腺并增加其患胰腺癌的风险。我们假设，父母在受孕前（父亲）和怀孕期间（母亲）摄入 OID 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 OID 是否与其后代成年后患胰腺癌的风险增加相关。目标 2：确定父亲在受孕前摄入 OID 是否与其后代成年后患胰腺癌的风险增加相关。目标 3：目标 3：确定父母消耗 OID 是否会导致其后代正常胰腺组织发生表观遗传重编程（DNA 甲基化和 miRNA 表达）。研究设计：我们的实验将使用 p48Cre/+ /LSL-KrasG12D/+ 胰腺癌小鼠模型。在实验 1 中，在怀孕期间（21 天），将分别向怀孕雌性喂食含有 17%（对照）或 58% 来自脂肪的能量（肥胖诱导饮食，OID）的 AIN93G 饮食。实验2中，雄性小鼠从断奶（3周龄）到性成熟（8周龄）期间喂食对照或OID饮食；此时，所有雄性小鼠将转为对照饮食并与雌性小鼠饲养在一起。实验2中的怀孕母鼠将在怀孕期间（21天）和分娩后饲喂对照饮食。两个实验中出生的幼崽将在出生后第 21 天断奶，并在实验期间喂食 AIN93G 对照饮食。后代的胰腺组织将在出生后第 50 天（PND）收集，并在 12 个月大时再次收集。病理学家将对 12 个月时收集的 p48Cre/+ /LSL-KrasG12D/+ 小鼠的胰腺组织进行胰腺原位癌 (PanIN) 和胰腺导管癌 (PDAC) 的评估，以确定亲本 OID 消耗对后代的影响胰腺肿瘤的发展。缺乏 p48Cre 或 LSL-KrasG12D 等位基因的同窝小鼠将用作对照。 PND50 上收集的胰腺组织将用于 microRNA 分析和全局甲基化分析，以确定亲本 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