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

项目摘要/摘要 血液和肝脏之间的血脂平衡在两个方向上的变化都会导致更高的发病风险 和死亡率。脂肪酸摄取增加导致甘油三酯在脂滴中积累 肝细胞与非酒精性脂肪性肝病(NAFLD)的发展。据估计，NAFLD有33%到 88%的患病率，已知会增加患2型糖尿病、血脂异常、高血压、 心血管疾病、慢性肾脏疾病、肝硬变、肝细胞癌和死亡率。这个 NAFLD的病因知之甚少，治疗方案的疗效也非常有限。另一方面， 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--这是主要的风险 导致心脏病发作的因素，美国每年有超过70万人死于心脏病。因此， 了解血脂失衡的可预防原因可能会对公众健康产生巨大影响。 在我们对实验室动物的实验中，我们发现发育过程中暴露在环境中 相关剂量的无处不在的环境阻燃剂，多溴联苯醚(PBDEs)，结果 与脂肪酸转位酶重编程相关的肝血脂平衡的永久性变化 CD36在肝脏中的表达--一种负责脂肪酸摄取的膜受体。我们还发现了 小鼠肝脏和人肝细胞癌中雷帕霉素机制靶点的激活 用多溴联苯醚提取细胞。我们最近在转基因小鼠身上的实验表明，PBDE可以诱导 许多脂代谢基因表达的永久性变化以及永久性血脂异常 依赖于mTOR。根据这一证据，我们推测在子宫内暴露于多溴二苯醚和卤化 人群中替代阻燃剂与胎儿组织和组织中mTOR活性的变化有关 会影响晚年的血脂水平。对于拟议的研究，我们将利用既定的手势预期 出生队列，旨在研究阻燃剂的发育毒性。斯泰特有大量的数据 产前和儿童暴露，形态测量，胎盘和血液样本的生物库，我们将 用来达到研究目的。在目标1中，我们将评估产前多溴联苯醚与卤代烃的关系 用mTOR蛋白激酶活性替代母血中的阻燃剂(可获得暴露数据) 胎儿胎盘。在目标2中，我们将评估产前血清多溴联苯醚与卤代谢物的相关性。 阻燃剂浓度与8-10岁儿童血脂谱和肝损伤标志物的关系。对两个人都是 目的我们将使用调解分析来评估机制。我们的结果将确定新的可预防的 血脂失衡的发育原因，并告知发育的宫内和早期生活干预 减少与血脂失衡相关的发病率和死亡率，如NAFLD和心脏病发作。就其本身而言 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.