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

项目总结/摘要 暴露于手性多氯联苯（PCBs）已被认为是发展神经发育障碍的危险因素;然而，在我们对调节神经发育障碍的代谢因素的理解方面存在根本性的差距。 神经毒性PCB对映体在发育中的大脑水平。因为体外研究表明多氯联苯可能 以对映选择性方式引起神经发育障碍，这一差距阻碍了流行病学研究 神经发育障碍和环境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）同工型水平和多态性如何影响手性特征（即，多氯联苯的神经毒性对映异构体水平）在靶组织中，并有助于手性特征的个体间变异性。很长的- 长期目标是确定PCB代谢的个体间差异如何影响环境暴露后PCB介导的神经发育障碍的易感性，并最终降低 这些疾病的负担。这个R21项目的目标是测试中心假设，即个体间 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的手性特征不同，并且手性特征在组织中相似 在一个人身上。提出研究的理由是，一旦P450酶系统之间的联系 和多氯联苯的手性特征已经建立，暴露和代谢之间的关系可以在有发展神经发育障碍风险的人群中进行研究。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进行测试：1）确定 人肝微粒体中肝P450酶的组成和PCBs在体外的对映体选择性代谢; 2）评估人死后尸体中PCB对映体水平之间的关系 肝和脑样品和P450在这些组织中的表达。在目标1中，我们将研究PCB的代谢 对映异构体与个别人肝微粒体和相关的代谢率P450酶的水平 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签名与P450酶的组成相关，并且在不同的组织中具有可比性。 来自同一个捐献者的组织这些研究将表征靶组织中P450酶系统的变化与人类中手性PCB特征差异之间的联系。拟议的研究是创新的，因为它使用最先进的方法来表征人体组织（如大脑）中多氯联苯的对映异构体组成，并推进了我们对潜在代谢过程的理解。这 这一贡献是重要的，因为了解P450酶和多氯联苯的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发展神经发育障碍的个体风险 并制定干预措施，减少其对个人、家庭和社会的影响。

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.