Epigenetic Regulation of Drug Metabolism by Developmental Exposure to PBDEs

多溴联苯醚发育暴露对药物代谢的表观遗传调控

• 批准号: 9265462
• 负责人: Yue Cui
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265462
• 关键词: Adult; Affect; Age; Cells; Chemicals; Child; Childhood; Chromatin; Cytochrome P450; DNA Methylation; Data; Development; Disease; Dose; Drug Kinetics; Drug Modulation; Drug Regulations; Drug Transport; Environment; Enzymes; Epigenetic Process; Excretory function; Exposure to; Flame Retardants; Gene Expression; Gene Expression Regulation; Gene Targeting; Generations; Genes; Genetic Transcription; Genotype; Goals; Growth; Hepatocyte; Hepatotoxicity; Histone Acetylation; Histones; Homeostasis; Human; Human Milk; In Vitro; Infant; Investigation; Knockout Mice; Knowledge; Ligands; Liver; Long-Term Effects; Mediating; Messenger RNA; Metabolism; Mission; Modification; Molecular; Mus; Neonatal; Newborn Infant; Nuclear Receptors; Nutrient; Organ; Outcome; Perinatal; Pharmaceutical Preparations; Population; Publishing; Quality of life; Reaction; Research; Role; Small Interfering RNA; Testing; Thyroid Hormones; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxicokinetics; United States National Institutes of Health; Wild Type Mouse; Work; Xenobiotics; absorption; constitutive androstane receptor; drug metabolism; drug modification; epigenetic drug; epigenetic memory; epigenetic regulation; genome-wide; high risk; histone methylation; humanized mouse; improved; interdisciplinary approach; liver development; neonatal exposure; neurotoxicity; novel; pediatric pharmacology; polybrominated diphenyl ether; pregnane X receptor; public health relevance; receptor; response; sensor; species difference; toxicant

 DESCRIPTION (provided by applicant): Developmental exposure to the flame-retardant polybrominated diphenyl ethers (PBDEs) has attracted growing concerns recently, because these highly persistent environmental toxicants are accumulated much more in infants through breast milk, and produce multiple detrimental effects. Although a growing body of research has been done regarding the toxicities of PBDEs themselves, little is known about the potential involvement of PBDEs in modulating the pharmacokinetics of drugs in newborns and children, who are at a much higher risk of adverse drug reactions. More importantly, there is no information regarding whether developmental exposure to PBDEs produces long lasting modifications of drug metabolism beyond childhood. We and others have identified that PBDEs are novel activators of the major xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive and rostane receptor (CAR). Neonatal activation of CAR results in epigenetic memory on histone methylation signatures and permanent change of drug metabolism in mouse liver, whereas PXR also regulates distinct epigenetic modifiers. Thus the objective of this research is to utilize multidisciplinary approaches to strategically investigate he epigenetic mechanisms of PBDEs in modulating the transcriptional activities of PXR and CAR and drug-processing capacities during and beyond the neonatal period on a genome-wide scale. Our central hypothesis is: neonatal exposure to PBDEs activates CAR and/or PXR, which in turn reprograms the ontogeny of critical chromatin epigenetic modifiers (such as DNA and histone methylation as well as histone acetylation), leading to epigenetic memory and altered ontogeny of drug-processing genes (DPGs), and long-term alterations in the pharmacokinetics and toxicokinetics beyond childhood. We will test this hypothesis in 3 specific aims: Aim 1 will use xeno-sensor null mice and second- generation sequencing to determine the roles of PXR and CAR in modulating the chromatin epigenetic signatures and expression of DPGs following neonatal exposure to PBDEs; Aim 2 will determine the effect of silencing key chromatin epigenetic modifiers on the expression of PXR- and CAR-target genes in PBDE- treated primary hepatocytes; Aim 3 will determine the role of neonatal PBDE exposure in modulating xeno- sensor activities, chromatin epigenetic signatures, expression of DPGs, and pharmacokinetics of drugs in xeno-sensor humanized mice and human hepatocytes. We will also examine the species-differences in PXR and CAR in response to PBDE exposure. Overall, the proposed work will unveil for the first time critical epigenetic and PXR/CAR-mediated mechanisms underlying PBDE-mediated regulation of drug metabolizing enzymes and transporters in newborns, and more importantly, determine the potential long-term effects caused by neonatal PBDE exposure on epigenetic memory and drug-processing capacities in adults. Our study is a paradigm shift in pediatric pharmacology, and will provide the first mechanistic investigations of PBDE-mediated modulation of drug metabolism and transport in newborns on a genome-wide scale.

 描述（由适用提供）：由于母乳中这些高度持久的环境有毒物质而在婴儿中积累了更多的持久性环境毒性，并且通过母乳积累了更多的问题，并产生多种有害作用。尽管对PBDE本身的毒性进行了越来越多的研究，但对于PBDE的潜在参与调节新生儿和儿童药物的药代动力学的潜在参与知之甚少，这些药物对不良药物反应的风险更高。更重要的是，没有关于在童年以后的药物代谢的持久修改是否持续的持久修饰。我们和其他人已经确定PBDE是主要的异种生物传感核受体怀孕X受体（PXR）和本构和rostaine受体（CAR）的新型激活剂。新生儿激活导致组蛋白甲基化特征的表观遗传记忆和小鼠肝脏中药物代谢的永久变化，而PXR还调节了不同的表观遗传修饰剂。这项研究的目的是利用多学科方法来战略研究PBDES的表观遗传机制，以调节新生儿范围内新生儿期间和新生儿期间PXR和CAR的转录活性以及药物处理能力。我们的中心假设是：对PBDE的新生儿暴露激活CAR和/或PXR，这又重新编程了关键的染色质染色质表观遗传学修饰剂（例如DNA和组蛋白甲基化以及组蛋白甲基化以及组蛋白乙酰化）的个体发育，并导致表观遗传记忆，并改变了遗传遗传学的原理，并改变了药物的基因和DPGS，以及DPGS和DPGS）和长期定性的基因和dpggs。少年时代以外的有毒因素。我们将在3个特定目的中检验这一假设：AIM 1将使用Xeno-Sensor Null小鼠和第二代测序来确定PXR和CAR在调节染色质表观遗传学特征和新生儿暴露后DPG表达中的作用； AIM 2将确定沉默的关键染色质表观遗传修饰剂对PBDE处理的原代肝细胞中PXR和靶标基因表达的影响； AIM 3将确定新生儿PBDE暴露在调节异种传感器活性，染色质表观遗传学特征，DPG表达以及药物在XENO-SENO传感器人性化小鼠和人肝细胞中的药代动力学的作用。我们还将检查PXR和CAR中的物种差异，以响应PBDE暴露。总体而言，拟议的工作将首次在新生儿中PBDE介导的药物代谢酶和转运蛋白的调节的基础的关键表观遗传学和PXR/CAR介导的机制，更重要的是，确定了由新生儿PBDE对表观基景记忆和成人毒品销售的潜在长期影响。我们的研究是小儿药理学的范式转移，将对PBDE介导的在全基因组范围内对药物代谢和新生儿的转运的调节进行首次机械研究。