Age-Dependent Role of Bisphenol A in Nonalcoholic Fatty Liver Disease

描述(由申请人提供)：21世纪社会面临的主要公共卫生挑战之一是代谢性疾病的日益流行。重要的是，肥胖的发病率正在急剧上升，导致糖尿病的流行，并增加了患代谢综合征和非酒精性脂肪性肝病(NAFLD)的风险，非酒精性脂肪性肝病(NAFLD)是甘油三酯(TG)在肝脏中的积累。双酚A(BPA)是一种在我们的环境中普遍存在的化学毒素，已在超过90%的美国人口的尿液中检测到。这种内分泌干扰物被认为与高胰岛素血症、肥胖症增加、糖尿病和临床上血清肝酶水平异常有关。目前，我们对双酚A暴露对肝脏基因表达、代谢和脂肪变性的影响知之甚少。该提案寻求资金来检验这样的假设，即围产期和/或终身双酚A暴露促进导致NAFLD的肝脏脂肪生成计划。拟议的研究将利用一个独特的机会--即计划在FDA国家毒理学研究中心(NCTR)进行的关于BPA对SpragueDawley大鼠影响的良好实验室实践(GLP)研究，在那里将产生两个单独的队列，每天通过灌胃暴露于几种不同剂量的BPA。孕妇在怀孕第6天开始灌胃，一直持续到出生那天。出生后，幼崽将直接从出生后第1天(PND1)开始灌胃，一直持续到PND21(第1组)。在其他动物(队列2)中，双酚A的口服将在整个生命过程中每天持续。其具体目的是确定围产期和终生双酚A暴露改变肝脏基因表达和促进肝脏脂质堆积的剂量(S)。我们将在6个月和12个月龄时确定两个队列中肝脏基因表达和脂肪代谢变化的时间顺序和进展。我们建议确定促进肝脏脂质代谢改变的相关基因和蛋白的表达。此外，我们将获得冷冻和固定的肝组织，用于组织学研究，以确定脂肪变性和炎症性病灶的存在，以及测量脂质过氧化和肝脏脂质堆积的标志的研究。这些数据将根据我们实验室已经从FDA/NCTR资助的动物研究中获得的血糖和胰岛素的血清测量，以及来自其他已经资助的研究人员的研究数据来查看，以确定脂肪组织重量、脂肪因子以及血清脂肪酸、甘油三酯和胆固醇水平。

DESCRIPTION (provided by applicant): One of the major public health challenges facing society in the 21st century is the increasing prevalence of metabolic diseases. Importantly, the incidence of obesity is rising dramatically leading to an epidemic of diabetes and an increased risk of developing metabolic syndrome and nonalcoholic fatty liver disease (NAFLD), which is the accumulation of triglyceride (TG) in the liver. Bisphenol A (BPA) is a ubiquitous chemical toxin in our environment and has been detected in the urine of greater than 90% of a cross section of the US population. This endocrine disruptor has been implicated in the development of hyperinsulinemia, increased adiposity, diabetes and clinically abnormal serum levels of liver enzymes. At the present time, we have limited knowledge of the effects of BPA exposure on hepatic gene expression, metabolism, and steatosis. This proposal seeks funds to test the hypothesis that perinatal and/or lifelong BPA exposure promotes the hepatic lipogenic program leading to NAFLD. The proposed research will take advantage of a unique opportunity- i.e., a planned good laboratory practice (GLP) study of BPA effects in Sprague Dawley rats that will be conducted at the FDA National Center for Toxicological Research (NCTR), where two separate cohorts exposed to several different doses of BPA by daily gavage will be generated. Gavage will begin in the pregnant mothers on gestational day 6 and continue through the day of birth. After birth, the pups will be gavaged directly beginning on postnatal day 1 (PND 1) continuing through PND21 (Cohort 1). In additional animals (Cohort 2), the oral gavage of BPA will continue daily throughout life. The specific aim is to determine the dose(s) of perinatal and lifelong BPA exposure that alters hepatic gene expression and promotes hepatic lipid accumulation. We will determine the chronology and progression of hepatic alterations in gene expression and lipid metabolism in the two cohorts at 6 and 12 months of age. We propose to determine relevant gene and protein expression that promote hepatic alterations in lipid metabolism. Additionally, we will obtain frozen and fixed liver tissues that will be used for histological studies to determine the presence of steatosis and inflammatory foci as well as studies to measure markers of lipid peroxidation and hepatic lipid accumulation. These data will be viewed in relation to the serum measurements of glucose and insulin that our laboratory has already obtained from a funded FDA/NCTR animal study, as well as data from studies by other already funded researchers, to determine adipose tissue weights, adipokines, and serum fatty acids, triglyceride, and cholesterol levels.