Programming Effects of Flame Retardants on Lipid Metabolism in a Longitudinal Birth Cohort

项目总结/摘要 血液和肝脏之间脂质平衡的任何一个方向的改变都会导致更高的发病风险 and mortality.脂肪酸摄取增加导致甘油三酯在脂滴中蓄积， 肝细胞和非酒精性脂肪性肝病（NAFLD）的发展。NAFLD估计有33%， 88%的患病率，已知会增加2型糖尿病、血脂异常、高血压、 心血管疾病、慢性肾病、肝硬化、肝细胞癌和死亡率。的 NAFLD的病因学知之甚少，治疗选择的疗效非常有限。另一方面，在一项研究中， 肝脏对脂肪酸的摄取减少可能导致高脂血症和动脉粥样硬化， 心脏病发作的因素，在美国每年有超过70万人死于这种疾病。因此 了解脂质失衡的可预防原因可能对公共卫生产生巨大影响。 在我们对实验室动物的实验中，我们发现， 普遍存在的环境阻燃剂多溴联苯醚（PBDEs）的相关剂量， 在与脂肪酸移位酶重编程相关的肝-血脂质平衡的永久性变化中 CD 36在肝脏中的表达--一种负责脂肪酸摄取的膜受体。我们还发现 雷帕霉素机制靶点（mTOR）在小鼠肝脏和人肝细胞癌中的活化 PBDE细胞。我们最近对转基因小鼠的实验表明， 许多脂质代谢基因表达的永久性变化以及永久性血脂异常， mTOR依赖性。基于这一证据，我们假设，在子宫内接触多溴联苯醚和卤化 人类中替代阻燃剂与胎儿组织中mTOR活性的改变有关， 影响以后的血脂水平。对于拟议的研究，我们将利用既定的盖斯特前瞻性 出生队列，旨在研究阻燃剂的发育毒性。盖斯特拥有大量数据， 产前和儿童期的暴露，形态学，以及胎盘和血液样本的生物库，我们将 以达到研究目的。在目标1中，我们将评估产前多溴联苯醚和卤化 母体血液中的替代阻燃剂（暴露数据可用）与mTOR蛋白激酶活性， 胎儿胎盘在目标2中，我们将评估产前血清中多溴二苯醚和卤化替代物之间的关系 8-10岁儿童中阻燃剂浓度与血脂谱和肝损伤标志物的关系。为 目的我们将使用调解分析来评估机制。我们的研究结果将确定新的可预防的 脂质失衡的发育原因，并告知子宫内和早期生命干预的发展， 降低与脂质失衡相关的发病率和死亡率，如NAFLD和心脏病发作。因此 我们的研究可能会对公共卫生和公共卫生支出产生巨大影响。

Project Summary/Abstract Alterations in the balance of lipids between blood and liver in either direction results in higher risk of morbidity and mortality. Increased uptake of fatty acids results in accumulation of triglycerides in lipid droplets of hepatocytes and non-alcoholic fatty liver disease (NAFLD) development. NAFLD is estimated to have 33% to 88% prevalence and is known to increase the risk of type 2 diabetes, dyslipidemia, hypertension, cardiovascular disease, chronic kidney disease, liver cirrhosis, hepatocellular carcinoma, and mortality. The etiology of NAFLD is poorly understood and treatment options have very limited efficacy. On the other hand, decreased uptake of fatty acids by liver may result in hyperlipidemia and atherosclerosis, - the primary risk factors for heart attack, with more than 700,000 deaths attributed to the disease in the US annually. Thus understanding of preventable causes of lipid imbalance may have tremendous consequences for public health. In our experiments with laboratory animals we discovered that developmental exposures to environmentally relevant doses of ubiquitous environmental flame retardants, polybrominated diphenyl ethers (PBDEs), result in permanent change in liver-blood balance of lipids associated with reprograming of fatty acid translocase CD36 expression in liver – a membrane receptor responsible for uptake of fatty acids. We have also found activation of mechanistic target of rapamycin (mTOR) in mouse livers and in human hepatocellular carcinoma cells by PBDE. Our recent experiments with genetically modified mice demonstrate that PBDE induced permanent changes in expression of many genes of lipid metabolism as well as permanent dyslipidemia are mTOR dependent. Base on this evidence we hypothesize that in utero exposure to PBDE and halogenated substitute flame retardants in human population is associated with altered mTOR activity in fetal tissues and affects lipid profile at later age. For the proposed study, we will leverage the established GESTE prospective birth cohort, designed to investigate developmental toxicity of flame retardants. GESTE has extensive data on prenatal and childhood exposures, morphometry, and a biobank of placenta and blood samples that we will use to achieve the study aims. In Aim 1 we will evaluate the associations of prenatal PBDE and halogenated substitute flame retardants in maternal blood (exposure data available) with mTOR protein kinase activity in fetal placentas. In Aim 2 we will evaluate the associations of prenatal serum PBDE and halogenated substitute flame retardant concentrations with lipid profiles and markers of liver injury in 8-10 years old children. For both aims we will use mediation analysis to evaluate mechanisms. Our results will identify new preventable developmental causes of lipid imbalance, and inform development of in utero and early life interventions to reduce morbidities and mortalities associated with lipid imbalance, such as NAFLD and heart attack. As such our research may have a tremendous impact on public health and public health spending.