Developmental exposure to Bisphenol A and susceptibility to liver injury

发育时期接触双酚 A 和对肝损伤的易感性

• 批准号: 8879721
• 负责人: Angela L Slitt
• 金额: $ 43.93万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879721
• 关键词: Adult; Affect; Anions; Antioxidants; Bile fluid; Biliary; Binding; Chemical Exposure; Chemicals; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Development; Diclofenac; Down-Regulation; Drug Metabolic Detoxication; Endocrine Disruptors; Environment; Excretory function; Exposure to; Family; Genetic; Goals; Health; Hepatic; Hepatocyte; Histone H3; Hormones; Human; Injury; Injury to Liver; Lactation; Life; Lithocholic Acid; Liver; Liver diseases; Longevity; Membrane; Metabolic Biotransformation; Modeling; Mus; Outcome; Perinatal; Perinatal Exposure; Pharmaceutical Preparations; Plastics; Play; Predisposition; Pregnancy; Process; Research; Resistance; Response Elements; Rhode Island; Role; Site; Testing; Toxic effect; Training; United States; Universities; Weaning; Work; bisphenol A; chromatin remodeling; chronic liver disease; drug clearance; drug metabolism; early life exposure; environmental chemical; hepatotoxin; histone deacetylase 2; improved; inhibitor/antagonist; innovation; liver injury; male; member; multidrug resistance-associated protein 2; overexpression; prevent; promoter; protein expression; public health relevance; restoration; tool

 DESCRIPTION (provided by applicant): Hepatic detoxification of chemicals and drugs from the body is accomplished by the hepatocytes via hepatic biotransformation and biliary excretion. ATP-binding cassette, sub-family C (CFTR/MRP), member 2 (ABCC2, aka MRP2), is a membrane-bound efflux transporter that transports organic anions out of the hepatocytes and into bile, playing critical role in this process. Numerous environmental chemicals, drugs, and endogenous metabolites are ABCC2 substrates. Disruption of ABCC2 function leads to disrupted bile flow, drug disposition, and drug-induced liver injury. We will be utilizing bispheno A (BPA), a plastics component, as a tool to understand how early life exposure to affects hepatic biliary excretion later in life. Our data illustrate that BPA exposure during gestation and lactation decreased liver ABCC2 expression and hepatic function of adult males that were >135 days old, which had no BPA exposure after weaning via increased histone deacetylase 2 (Hdac2) and decreased acetylated Histone H3 at the mouse ABCC2 promoter. In this proposal, we seek to ask whether our observation with BPA exposure has a toxicological consequence to liver and better understand whether modulation of ABCC2 and Hdac2 expression/function can restore the observed decrease in biliary excretion. We hypothesize that BPA exposure decreases biliary expression via down regulation of ABCC2 promoter activity via Hdac2 and Nrf2-dependent mechanisms. The observed decrease in biliary excretion increases susceptibility to hepatotoxicants that undergo biliary excretion. Specific Aim 1 will characterize the role of ABCC2 in adult liver excretion after perinatal BPA exposure. First, we will test whether restoration of ABCC2 protein expression in adult male progeny will restore the observed decrease in biliary excretion caused by developmental BPA exposure. We will next test whether perinatal BPA exposure alters susceptibility of adult male progeny to liver injury induced by hepatotoxicants. Specific Aim 2 will characterize whether of NRF2 and histone deacetylase 2 increase Abcc2 expression and can restore biliary excretion. Our BPA exposure model elucidated that BPA increases Hdac2 association at the mouse ABCC2 promoter. We will further determine whether Hdac2 is a modulator of ABCC2 expression in this model through genetic and pharmacological approaches and whether forced expression of NRF2 can restore ABCC2 expression and bile flow. Outcome: This work will significantly impact the field of liver health - demonstrating: 1) hepatic biliary function via ABCC2 is susceptible to "reprogramming" by chemical exposure, 2) early life exposure changes susceptibility to liver injury later in life, ) Identify Hdac2 as a potential target to restore bile flow. AREA impact: This project will provide an excellent intellectual and technical training environment for undergraduates and enhance the research capacity at the University of Rhode Island.

 描述（通过应用提供）：从体内的化学物质和药物对肝脏排毒是通过肝细胞通过肝细胞和胆道极端的肝细胞来完成的。 ATP结合盒，亚族C（CFTR/MRP），成员2（ABCC2，AKA MRP2）是一种膜结合的外排运输蛋白，将有机阴离子从肝细胞中运出并进入胆汁，在此过程中起着至关重要的作用。许多环境化学物质，药物和内源代谢产物是ABCC2底物。 ABCC2功能的破坏会导致胆汁流，药物处置和药物诱导的肝损伤的破坏。我们将使用塑料组件Bispheno A（BPA）作为一种工具，以了解早期生命后期生命的早期暴露于后期的极端情况。我们的数据表明，妊娠期间的BPA暴露 泌乳降低了成年雄性的肝脏ABCC2表达和肝功能> 135天大，通过增加的组蛋白脱乙酰基酶2（HDAC2）断奶后没有BPA暴露，并改善了小鼠ABCC2启动子的乙酰化组蛋白H3。在此提案中，我们试图询问我们对BPA暴露的观察是否对肝脏具有毒理学后果，并更好地理解ABCC2和HDAC2表达/功能的调节是否可以恢复胆汁排泄的观察到的降低。我们假设BPA暴露通过降低HDAC2和NRF2依赖性机制来降低ABCC2启动子活性来降低胆道的表达。观察到的胆汁排泄的降低会增加对经历胆道排泄的肝毒性的敏感性。特定的目标1将表征ABCC2在围产期BPA暴露后成人肝脏排泄中的作用。首先，我们将测试成年男性后代中ABCC2蛋白表达的恢复是否会恢复因发育性BPA暴露引起的胆汁排泄所观察到的减少。我们下次测试围产期BPA暴露是否会改变成年男性后代对肝毒性造成的肝损伤的敏感性。特定的目标2将表征NRF2和组蛋白脱乙酰基酶2是否会增加ABCC2的表达并可以恢复胆道排泄。我们的BPA暴露模型阐明了BPA增加了小鼠ABCC2启动子的HDAC2关联。我们将进一步确定HDAC2是否通过遗传和药物方法在该模型中是ABCC2表达的调节剂，以及NRF2强迫表达是否可以恢复ABCC2的表达和胆汁流。结果：这项工作将显着影响肝脏健康领域 - 证明：1）通过ABCC2通过ABCC2通过化学暴露“重编程”的肝胆道功能很容易受到“重新编程”，2）早期生命暴露会改变生命后期生命损伤的敏感性；区域影响：该项目将为本科生提供出色的智力和技术培训环境，并提高罗德岛大学的研究能力。