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

双酚 A 在非酒精性脂肪肝中的年龄依赖性作用

• 批准号: 8490803
• 负责人: ANDREW S GREENBERG
• 金额: $ 7.55万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490803
• 关键词: Adipose tissue; Adult; Age-Months; Animal Experimentation; Animals; Back; Birth; Body Weight; Body fat; Chemicals; Cholesterol; Cholesterol Esters; Chronology; Data; Development; Diabetes Mellitus; Dose; Endocrine Disruptors; Environment; Enzymes; Epidemic; Event; Fatty Acids; Fatty acid glycerol esters; Freezing; Funding; Gene Expression; Glucose; Goals; Hepatic; Hyperinsulinism; Incidence; Inflammatory; Insulin; Islet Cell; Islets of Langerhans; Knowledge; Laboratories; Letters; Life; Lipid Peroxidation; Lipids; Liver; Liver Dysfunction; Liver diseases; Measurement; Measures; Metabolic Diseases; Metabolic syndrome; Metabolism; Mothers; Mus; Obesity; Oral; Perinatal; Population; Prevalence; Public Health; Rattus; Reporting; Research; Research Personnel; Risk; Role; Serum; Societies; Sprague-Dawley Rats; Testing; Time; Tissues; Toxin; Triglycerides; Urine; Weight; adipokines; age related; bisphenol A; cohort; good laboratory practice; lipid metabolism; liver function; male; non-alcoholic fatty liver; postnatal; pregnant; programs; protein expression; public health relevance; pup; research facility

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.

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患病率日益增加。重要的是，肥胖症的发病率急剧上升，导致糖尿病的流行，以及发展代谢综合征和非酒精性脂肪性肝病（NAFLD）的风险增加，NAFLD是甘油三酯（TG）在肝脏中的积累。双酚A（BPA）是一种普遍存在于我们环境中的化学毒素，在美国人口中超过90%的人的尿液中检测到。这种内分泌干扰物与高胰岛素血症、肥胖症增加、糖尿病和临床异常血清肝酶水平的发展有关。目前，我们对BPA暴露对肝脏基因表达、代谢和脂肪变性的影响了解有限。该提案寻求资金来测试围产期和/或终身BPA暴露促进导致NAFLD的肝脏脂肪生成程序的假设。拟议的研究将利用一个独特的机会-即，在FDA国家毒理学研究中心（NCTR）进行的一项计划中的Sprague道利大鼠中BPA效应的良好实验室规范（GLP）研究，其中将产生两个通过每日灌胃暴露于几种不同剂量BPA的单独队列。在妊娠第6天开始开始灌胃，并持续至出生当天。出生后，从出生后第1天（PND 1）开始直接灌胃幼仔，持续至PND 21（队列1）。在其他动物（队列2）中，BPA经口灌胃将在整个生命周期内每天持续。具体目的是确定围产期和终身BPA暴露的剂量，改变肝脏基因表达和促进肝脏脂质积累。我们将在6月龄和12月龄时确定两个队列中基因表达和脂质代谢的肝脏改变的时间顺序和进展。我们建议确定相关基因和蛋白质表达，促进肝脏脂质代谢的变化。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灶的存在，以及测量脂质过氧化和肝脂质蓄积标志物的研究。这些数据将与我们实验室已经从FDA/NCTR资助的动物研究中获得的葡萄糖和胰岛素的血清测量值以及其他已经资助的研究人员的研究数据相关，以确定脂肪组织重量，脂肪因子和血清脂肪酸，甘油三酯和胆固醇水平。