Developmental exposure to Bisphenol A and susceptibility to liver injury

 描述（由申请方提供）：肝细胞通过肝脏生物转化和胆汁排泄完成体内化学品和药物的肝脏解毒。ATP结合盒，亚家族C（CFTR/MRP），成员2（ABCC 2，aka MRP 2），是将有机阴离子从肝细胞转运到胆汁中的膜结合外排转运蛋白，在该过程中起关键作用。许多环境化学物质、药物和内源性代谢物都是ABCC 2的底物。ABCC 2功能的破坏导致胆汁流动、药物处置和药物诱导的肝损伤中断。我们将利用双酚A（BPA），一种塑料成分，作为一种工具来了解生命早期暴露于双酚A如何影响生命后期的肝脏胆汁排泄。我们的数据表明，怀孕期间接触BPA， 哺乳降低了>135日龄的成年雄性的肝脏ABCC 2表达和肝功能，这些雄性在断奶后没有BPA暴露，这是通过增加组蛋白去乙酰化酶2（Hdac 2）和减少小鼠ABCC 2启动子处的乙酰化组蛋白H3实现的。在本提案中，我们试图询问BPA暴露的观察结果是否对肝脏具有毒理学后果，并更好地了解ABCC 2和Hdac 2表达/功能的调节是否可以恢复观察到的胆汁排泄减少。我们假设BPA暴露通过Hdac 2和Nrf 2依赖性机制下调ABCC 2启动子活性来降低胆汁表达。观察到的胆汁排泄减少增加了对经过胆汁排泄的肝毒物的敏感性。具体目标1将描述ABCC 2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ABCC 2蛋白在成年雄性后代中表达的恢复是否会恢复由发育BPA暴露引起的胆汁排泄减少。我们接下来将测试围产期BPA暴露是否会改变成年男性后代对肝毒物诱导的肝损伤的易感性。特异性目的2将表征NRF 2和组蛋白脱乙酰酶2是否增加Abcc 2表达并可以恢复胆汁排泄。我们的BPA暴露模型阐明了BPA增加了小鼠ABCC 2启动子处的Hdac 2缔合。我们将通过遗传和药理学方法进一步确定Hdac 2是否是该模型中ABCC 2表达的调节剂，以及NRF 2的强制表达是否可以恢复ABCC 2表达和胆汁流量。结果：这项工作将对肝脏健康领域产生重大影响-证明：1）通过ABCC 2实现的肝胆功能易受化学暴露的“重编程”影响，2）生命早期暴露会改变生命后期对肝损伤的易感性，）将Hdac 2鉴定为恢复胆汁流量的潜在靶点。区域影响：该项目将为本科生提供良好的智力和技术培训环境，并提高罗得岛大学的研究能力。

 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.