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: 9125839
• 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/9125839
• 关键词: Adult; Affect; Age; Cells; Chemicals; Child; Childhood; Chromatin; Cytochrome P450; DNA Methylation; Data; Development; Disease; Dose; Drug Kinetics; Drug Receptors; Drug Regulations; Drug Transport; Environment; Enzymes; Epigenetic Process; Excretory function; Exposure to; Flame Retardants; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Generations; Genetic Transcription; Genotype; Goals; Growth; Health; 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; Process; Processed Genes; Publishing; Quality of life; Reaction; Research; Role; Testing; Thyroid Hormones; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxicokinetics; Wild Type Mouse; Work; Xenobiotics; absorption; constitutive androstane receptor; drug metabolism; 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; 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（由申请人提供）：由于这些高度持久性的环境毒物通过母乳在婴儿体内积累得更多，并产生多种有害影响，因此，最近对阻燃剂多溴二苯醚（PBDEs）的发育暴露引起了越来越多的关注。尽管对多溴二苯醚本身的毒性进行了越来越多的研究，但人们对多溴二苯醚可能参与调节新生儿和儿童体内药物的药代动力学知之甚少，因为新生儿和儿童发生药物不良反应的风险要高得多。更重要的是，没有资料说明儿童期以后在发育过程中接触多溴二苯醚是否会对药物代谢产生长期影响。我们和其他人已经发现，多溴二苯醚是主要的异生物质敏感核受体的新型激活剂，包括PXR和CAR。CAR的新生激活导致小鼠肝脏中组蛋白甲基化特征的表观遗传记忆和药物代谢的永久变化，而PXR也调节不同的表观遗传修饰剂。因此，本研究的目的是利用多学科的方法，战略性地调查他的表观遗传机制的多溴二苯醚在调节转录活动的PXR和CAR和药物加工能力在新生儿期间和以后的全基因组范围内。我们的中心假设是：新生儿接触多溴联苯醚会激活CAR和/或PXR，进而重新编程关键染色质表观遗传修饰剂（如DNA和组蛋白甲基化以及组蛋白乙酰化）的个体发生，导致表观遗传记忆和药物加工基因（DPG）的个体发生改变，以及童年以后药代动力学和毒理学的长期改变。我们将在3个具体目标中测试这一假设：目标1将使用异种传感器无效小鼠和第二代测序来确定PXR和CAR在新生儿暴露于PBDE后调节染色质表观遗传特征和DPG表达中的作用;目标2将确定沉默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CAR靶基因表达的影响;目标3将确定新生儿多溴二苯醚暴露在调节异种传感器活性、染色质表观遗传特征、DPG表达以及异种传感器人源化小鼠和人肝细胞中药物的药代动力学方面的作用。我们还将研究PXR和CAR对PBDE暴露的反应的物种差异。总体而言，拟议的工作将首次揭示关键的表观遗传和PXR/CAR介导的机制，这些机制是多溴二苯醚介导的新生儿药物代谢酶和转运蛋白调节的基础，更重要的是，确定新生儿多溴二苯醚暴露对成人表观遗传记忆和药物处理能力造成的潜在长期影响。我们的研究是儿科药理学的一个范式转变，并将在全基因组范围内提供多溴联苯醚介导的新生儿药物代谢和转运调节的第一个机制调查。