PCB Enantiomers Implicated in Neurodevelopmental Disorders: Identification of Individual Metabolic Factors that Determine Risk and Vulnerability

与神经发育障碍有关的 PCB 对映体：确定决定风险和脆弱性的个体代谢因素

• 批准号: 9314179
• 负责人: HANS-JOACHIM LEHMLER
• 金额: $ 22.39万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314179
• 关键词: Affect; Air; Animals; Attentional deficit; Autopsy; Biometry; Brain; Breathing; CYP2B6 gene; Chemicals; Complex; Cytochrome P450; Data; Diet; Dietary Intervention; Disease; Environment; Environmental Exposure; Environmental Pollution; Environmental Risk Factor; Enzymes; Exposure to; Family; Future; Genetic; Genetic Polymorphism; Goals; Health; Hepatic; Human; Image; In Vitro; Incidence; Individual; Individual Differences; Intervention; Knowledge; Learning Disabilities; Link; Liver; Liver Microsomes; Measures; Mediating; Metabolic; Metabolism; Methods; Mission; Molecular Biology; Neurodevelopmental Disorder; Oral; Organism; Pharmacology; Play; Polychlorinated Biphenyls; Population; Populations at Risk; Positioning Attribute; Predisposition; Protein Isoforms; Proteins; Public Health; Publishing; Research; Risk; Risk Factors; Rodent; Role; Route; Sampling; Severities; Societies; Source; System; Techniques; Testing; Tissue Sample; Tissues; Toxic effect; Toxicology; United States National Institutes of Health; Variant; base; brain tissue; burden of illness; developmental neurotoxicity; enantiomer; epidemiology study; expectation; experimental study; human disease; human tissue; innovation; metabolic abnormality assessment; neurodevelopment; neurotoxic; pollutant; prevent

PROJECT SUMMARY/ABSTRACT Exposure to chiral polychlorinated biphenyls (PCBs) has been implicated as risk factor for developing neurodevelopmental disorders; however, there is a fundamental gap in our understanding of metabolic factors that modulate levels of neurotoxic PCB enantiomers in the developing brain. Because in vitro studies suggest that PCBs may cause neurodevelopmental disorders in an enantioselective manner, this gap prevents epidemiological studies from fully characterizing associations between neurodevelopmental disorders and environmental PCB exposures. Therefore, there is a critical need to understand how differences in metabolic factors, in particular cytochrome P450 (P450) isoform levels and polymorphisms, affect chiral signatures (i.e., levels of neurotoxic enantiomers of PCBs) in target tissues and contribute to an inter-individual variability in chiral signatures. The long- term goal is to determine how inter-individual differences in enantioselective PCB metabolism affect the susceptibility to PCB-mediated neurodevelopmental disorders following environmental exposures and, ultimately, reduce the burden of these diseases. The objective of this R21 project is to test the central hypothesis that inter-individual differences in the composition of the P450 enzyme system, including both P450 isoform levels and polymorphisms, result in different chiral signatures of retained PCBs, and that chiral signatures are similar across tissues within an individual. The rationale for the proposed studies is that, once the link between the P450 enzyme system and PCB chiral signature has been established, the relationship between exposure and metabolism can be studied in a human population at risk of developing a neurodevelopmental disorder. Guided by strong preliminary data, the central hypothesis will be tested by pursuing two Specific Aims: 1) Determine the relationship between the composition of hepatic P450 enzymes in individual human liver microsomes and the enantioselective metabolism of PCBs in vitro; and 2) assess the relationship between levels of PCB enantiomers in human postmortem liver and brain samples and P450 expression in these tissues. In Aim 1, we will study the metabolism of PCB enantiomers with individual human liver microsomes and relate metabolism rates to levels of P450 enzymes and polymorphisms. In Aim 2, we will measure levels of PCB enantiomers in postmortem tissues to demonstrate that chiral PCB signatures are related to the composition of P450 enzymes and comparable in different tissues from the same donor. These studies will characterize the link between variations in the P450 enzyme system in target tissues and differences in the chiral PCB signatures among humans. The proposed research is innovative because it uses state-of-the-art methods to characterize the enantiomer composition of PCBs in human tissues, such as the brain, and advances our understanding of the underlying metabolic processes. This contribution is significant because understanding the link between P450 enzymes and levels of neurotoxic enantiomers of PCBs will allow us to further study individual risks of developing a neurodevelopmental disorder and develop interventions to reduce their impact on individuals, families and society.

项目概要/摘要 接触手性多氯联苯 (PCB) 被认为是发生神经发育障碍的危险因素；然而，我们对调节代谢因素的理解存在根本差距 发育中大脑中神经毒性 PCB 对映体的水平。因为体外研究表明 PCB 可能 以对映选择性方式引起神经发育障碍，这种差距阻碍了流行病学研究 充分表征神经发育障碍与环境 PCB 暴露之间的关联。因此，迫切需要了解代谢因素的差异，特别是细胞色素 P450 (P450) 亚型水平和多态性，如何影响目标组织中的手性特征（即 PCB 的神经毒性对映体水平），并有助于个体间的差异手性特征的可变性。长- 术语目标是确定对映选择性 PCB 代谢的个体间差异如何影响环境暴露后对 PCB 介导的神经发育障碍的易感性，并最终减少 这些疾病的负担。这个 R21 项目的目标是检验个体间的中心假设 P450酶系统组成的差异，包括P450亚型水平和多态性，导致保留的PCB具有不同的手性特征，并且跨组织的手性特征是相似的 一个人之内。拟议研究的基本原理是，一旦 P450 酶系统之间的联系 并且 PCB 手性特征已经建立，可以在有神经发育障碍风险的人群中研究暴露与代谢之间的关系。在强有力的初步数据的指导下， 中心假设将通过追求两个具体目标来检验：1）确定 人肝微粒体中肝 P450 酶的组成以及 PCB 的体外对映选择性代谢； 2) 评估人类死后 PCB 对映体水平之间的关系 肝脏和大脑样本以及这些组织中 P450 的表达。在目标1中，我们将研究PCB的代谢 与个体人肝微粒体的对映体并将代谢率与 P450 酶水平相关 和多态性。在目标 2 中，我们将测量死后组织中 PCB 对映体的水平，以证明手性 PCB 特征与 P450 酶的组成相关，并且在不同的环境中具有可比性。 来自同一捐赠者的组织。这些研究将表征靶组织中 P450 酶系统的变异与人类手性 PCB 特征的差异之间的联系。拟议的研究具有创新性，因为它使用最先进的方法来表征人体组织（例如大脑）中 PCB 的对映体组成，并增进了我们对潜在代谢过程的理解。这 贡献意义重大，因为了解 P450 酶与 PCB 神经毒性对映体水平之间的联系将使我们能够进一步研究患神经发育障碍的个体风险 并制定干预措施以减少其对个人、家庭和社会的影响。