Epigenetic Regulation of Drug Metabolism by Developmental Exposure to PBDEs

 描述(申请人提供)：发育过程中接触阻燃剂多溴二苯醚(PBDEs)最近引起了越来越多的关注，因为这些高度持久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。尽管对多溴二苯醚本身的毒性进行了越来越多的研究，但对多溴二苯醚在调节药物在新生儿和儿童中的药代动力学的潜在参与知之甚少，因为他们面临着更高的药物不良反应风险。更重要的是，目前还没有关于发育过程中暴露于多溴二苯醚是否会对儿童以后的药物代谢产生长期影响的信息。我们和其他人已经确定，多溴二苯醚是主要的异物敏感核受体孕烷X受体(PXR)和构成受体和雌激素受体(CAR)的新激活剂。新生儿激活CAR导致组蛋白甲基化特征的表观遗传记忆和小鼠肝脏药物代谢的永久性变化，而PXR也调节不同的表观遗传修饰物。因此，本研究的目的是利用多学科方法在全基因组范围内战略性地研究多溴二苯醚在调节PXR和CAR转录活动中的表观遗传机制以及在新生儿期和之后的药物处理能力。我们的中心假设是：新生儿暴露于多溴二苯醚会激活CAR和/或PXR，进而对关键的染色质表观遗传修饰物(如DNA和组蛋白甲基化以及组蛋白乙酰化)的个体发生进行重新编程，导致表观遗传记忆和药物加工基因(DPG)的个体发生改变，以及儿童以后药代动力学和毒物动力学的长期变化。我们将在3个特定目标中检验这一假说：目标1将使用异种传感器缺失小鼠和第二代测序来确定PXR和CAR在调节新生儿暴露于多溴二苯醚后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物对多溴二苯醚治疗的原代肝细胞中PXR和CAR靶基因表达的影响；目标3将确定新生儿多溴联苯醚暴露在调节异种传感器活性、染色质表观特征、DPG的表达和药物在异种传感器人源化小鼠和人肝细胞中的药代动力学中的作用。我们还将研究PXR和CAR对多溴联苯醚暴露的物种差异。总体而言，拟议的工作将首次揭示关键的表观遗传学和PXR/CAR介导的机制，潜在的PBDE介导的调节新生儿的药物代谢酶和转运蛋白，更重要的是，确定潜在的长期影响，新生儿多溴二苯醚暴露对表观遗传记忆和药物处理能力的成年人。我们的研究是儿科药理学的一次范式转变，并将首次在全基因组范围内提供PBDE介导的新生儿药物代谢和运输调节的机制研究。

 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.