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

 描述(申请人提供)：儿童肥胖症患病率在过去三十年中显著增加。肥胖儿童超重的可能性是成年人的4-6倍，成人患代谢合并症的风险更高，如非酒精性脂肪肝(NAFLD)。在美国儿童中，非酒精性脂肪肝的患病率估计为9%，但在肥胖儿童中上升到38%。早期肝脏脂肪变性的特征是脂肪堆积、胰岛素抵抗和肝脏氧化应激水平升高。产前暴露于化学和饮食因素会通过表观遗传机制影响代谢规划，改变一生中的代谢反应。类似的重编程机制可能会改变子代在子宫暴露后的氧化应激反应，但这一点尚未被研究。利用活体小鼠模型，这项建议调查了在子宫内暴露于内分泌干扰物，如双酚A(BPA)，以及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。虽然成年期接触BPA和高脂饮食(HFD)与氧化应激增加有关，但它们通过胎儿氧化还原敏感基因的表观遗传重新编程而影响终生NAFLD风险的潜力尚不清楚。饮食和毒物暴露的相互作用并不常见；因此，拟议的模型将为饮食缓解或加剧产前暴露引起的细胞内和基因组变化的能力提供新的见解。测量小鼠活体和血液样本中多种类型的组织特异性氧化反应(例如，氧化还原电位、蛋白质硫醇氧化、脂质氧化)将有助于深入了解产前双酚A和高脂蛋白同时暴露对氧化还原调节的胰岛素抵抗、基因甲基化和表达的影响，以及随后在敏感生命阶段纵向上脂类成分的变化。胎儿氧化应激和胰岛素反应的程序化对包括NAFLD在内的慢性疾病具有广泛的意义。提高对这一早期生活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。F31博士前奖学金为我提供了扩大目前博士生培训和研究潜力的机会。主要目标是在我目前在表观遗传学、毒理学、营养学和新型脂类方面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学习面向多个受众的研究翻译方法，以及提高我的领导力和管理技能。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，可以更好地解释人口中氧化应激反应的增加及其与胰岛素抵抗的联系，同时慢性疾病的发病率也在上升，包括肥胖症和非酒精性脂肪肝。

 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.