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Fetal Programming of Oxidative Stress Response via Diet and Bisphenol A Exposure

通过饮食和双酚 A 暴露对氧化应激反应进行胎儿编程

基本信息

批准号：
9120263
负责人：
Elizabeth Hoit Marchlewicz
金额：
$ 3.06万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9120263
关键词：
Address Adolescence Adolescent Adult Animal Model Bioavailable Biological Biological Markers Birth Blood Blood specimen Buffers Candidate Disease Gene Central obesity Chemical Exposure Chemicals Child Chronic Disease Cluster Analysis Comorbidity DNA Methylation DNA Sequence Alteration Data Analyses Data Set Development Diet Dietary Factors Dietary Fats Early Diagnosis Endocrine Disruptors Environment Environmental Risk Factor Enzymes Epidemic Epigenetic Process Equation Etiology Evaluation Exposure to Fatty Liver Fatty acid glycerol esters Fellowship Financial compensation Gene Expression Gene Expression Regulation Genes Genetic Transcription Glutathione Disulfide Goals Hepatic High Fat Diet Histocompatibility Testing Histology Homeostasis Human Hypertension Incidence Individual Insulin Insulin Resistance Leadership Life Linear Models Link Lipids Liver Liver diseases Maps Measurement Measures Mediating Mediator of activation protein Mediterranean Diet Metabolic Methods Methylation Modeling Mus Non-Insulin-Dependent Diabetes Mellitus OGTT Obesity Outcome Overweight Oxidation-Reduction Oxidative Stress Oxidative Stress Pathway Pathway Analysis Pathway interactions Perinatal Exposure Phenotype Plasma Play Population Pregnancy Prevalence Prevention Prevention program Process Proteins Public Health Applications Research Research Research Project Grants Research Training Risk Risk Marker Role Sensitivity and Specificity Shotguns Staging Sulfhydryl Compounds Techniques Time Tissues Toxicant exposure Toxicology Training Translational Research Triglycerides United States biological adaptation to stress bisphenol A career chronic liver disease fasting glucose fetal fetal programming improved in utero in vivo insight insulin sensitivity insulin signaling interest intervention program learning strategy lipid metabolism longitudinal analysis mRNA Expression minimally invasive mouse model non-alcoholic fatty liver novel novel strategies nutrition obesity in children offspring oxidation postnatal pre-doctoral prenatal prenatal exposure prenatal intervention programs public health relevance pup resistance gene response skills toxicant western diet

项目摘要

DESCRIPTION (provided by applicant): Childhood obesity prevalence has increased significantly over the past three decades. Obese children are 4-6 times more likely to become overweight or obese adults with greater risk of metabolic co-morbidities, such as non-alcoholic fatty liver disease (NAFLD). In U.S. children NAFLD prevalence is estimated to be 9%, but increases to 38% among obese children. Early stage hepatic steatosis is characterized by lipid accumulation, insulin resistance, and elevated levels of oxidative stress in the liver. Prenatal exposure to chemical and dietary factors can impact metabolic programming via epigenetic mechanisms, altering metabolic responses across life. A similar reprogramming mechanism may alter oxidative stress responses in offspring following in utero exposures, but this has not been studied. Using an in vivo mouse model, this proposal investigates mechanisms contributing to in utero exposures to endocrine disrupting chemicals, e.g. bisphenol A (BPA), and high fat Western and Mediterranean diets and altered oxidative stress and insulin response in adolescence and adulthood. While BPA and high fat diet (HFD) exposures in adulthood have been associated with increased oxidative stress, their potential to impact lifelong risk of NAFLD via fetal epigenetic reprogramming of redox sensitive genes is not understood. Interactions of diet and toxicant exposures are not commonly studied; thus the proposed model will provide novel insight into the ability of diets to mitigate or exacerbate intracellular and genomic alterations resulting from prenatal exposures. Measuring multiple types of tissue-specific oxidative responses (e.g. redox potentials, protein thiol oxidation, lipid oxidation) in mouse live and blood samples will provide insight into the effects that concurrent prenatal BPA and HFD exposures have on redox- regulated insulin resistance, gene methylation and expression, and subsequent changes in lipid composition, longitudinally across sensitive life stages. Fetal programming of oxidative stress and insulin response has wide-ranging implications for chronic diseases, including NAFLD. Improved understanding of this early life programming and the ability of diet to mitigate detrimental toxicant effects will promote development of prenatal intervention and prevention programs. This F31 Predoctoral Fellowship provides the opportunity to expand my current doctoral training and research potential. The primary goal is to build on my current multi-disciplinary research skills in epigenetics, toxicology, nutrition, and novel lipidomcs to study sensitive oxidative stress measurement techniques, data analysis methods of repeated measures, and merging large datasets. Career goals facilitated by this fellowship include protected time to learn methods for research translation to multiple audiences and to improve my leadership and management skills. The comprehensive training plan and proposed research project will examine a novel developmental pathway and mechanisms that could better explain the increase in oxidative stress response and its connection to insulin resistance across the population concurrent with rising incidence of chronic diseases, including obesity and NAFLD.

描述（由申请人提供）：在过去的三十年中，儿童肥胖症的患病率显著增加。肥胖儿童超重或肥胖成人的可能性高4-6倍，代谢性共病的风险更大，如非酒精性脂肪性肝病（NAFLD）。在美国儿童中，NAFLD患病率估计为9%，但在肥胖儿童中增加到38%。早期肝脂肪变性的特征在于肝脏中脂质积聚、胰岛素抵抗和氧化应激水平升高。产前暴露于化学和饮食因素可以通过表观遗传机制影响代谢程序，改变一生的代谢反应。类似的重编程机制可能会改变子宫内暴露后后代的氧化应激反应，但尚未研究。使用体内小鼠模型，该提案调查了导致子宫内暴露于内分泌干扰化学品（例如双酚A（BPA））和高脂肪西方和地中海饮食以及青春期和成年期氧化应激和胰岛素反应改变的机制。虽然BPA和高脂饮食（HFD）暴露在成年期与氧化应激增加有关，但其通过氧化还原敏感基因的胎儿表观遗传重编程影响NAFLD终身风险的潜力尚不清楚。饮食和有毒物质暴露的相互作用并不常见的研究，因此，拟议的模型将提供新的见解饮食的能力，以减轻或加剧细胞内和基因组的变化，导致产前曝光。测量小鼠肝脏和血液样品中多种类型的组织特异性氧化反应（例如氧化还原电位、蛋白硫醇氧化、脂质氧化）将提供对同时产前BPA和HFD暴露对氧化还原调节的胰岛素抵抗、基因甲基化和表达以及脂质组成的后续变化的影响的深入了解，纵向跨越敏感的生命阶段。氧化应激和胰岛素反应的胎儿编程对慢性疾病（包括NAFLD）具有广泛的影响。提高对这种早期生命规划的理解以及饮食减轻有害毒物影响的能力将促进产前干预和预防计划的发展。这个F31博士前奖学金提供了机会，以扩大我目前的博士培训和研究潜力。主要目标是建立在我目前在表观遗传学，毒理学，营养学和新型脂质组学的多学科研究技能的基础上，研究敏感的氧化应激测量技术，重复测量的数据分析方法，以及合并大型数据集。该奖学金促进的职业目标包括有保护的时间来学习向多个受众进行研究翻译的方法，并提高我的领导和管理技能。全面的培训计划和拟议的研究项目将研究一种新的发展途径和机制，可以更好地解释氧化应激反应的增加及其与人群胰岛素抵抗的联系，同时慢性疾病的发病率上升，包括肥胖和NAFLD。