Molecular and Cellular Basis of PCB Developmental Neurotoxicity

PCB 发育神经毒性的分子和细胞基础

• 批准号: 10319025
• 负责人: HANS-JOACHIM LEHMLER
• 金额: $ 61.26万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10319025
• 关键词: Address; Adolescent; Air; Animals; Apoptosis; Behavior; Brain; CREB1 gene; CYP2B6 gene; Child; Clinical Data; Coculture Techniques; Cognitive; Cytochrome P450; Data; Development; Dose; Engineering; Environment; Environmental Pollution; Enzymes; Exposure to; Female; Food; Genetic Polymorphism; Goals; Growth; Health; Hepatic; Hepatocyte; Heritability; Hippocampus (Brain); Human; In Vitro; Industrialization; Knockout Mice; Knowledge; Lactation; Light; Link; Mediating; Metabolism; Mission; Molecular; Molecular Target; Morphogenesis; Mus; Mutation; Neurodevelopmental Disorder; Neuroglia; Neurons; Neurotoxins; Organism; Outcome; Outcome Study; Oxidative Stress; Parents; Pharmacology; Polychlorinated Biphenyls; Population; Positioning Attribute; Pregnancy; Pregnant Women; Process; Protein Isoforms; Proteins; Public Health; Recombinants; Research; Risk; Role; Ryanodine Receptor Calcium Release Channel; Sampling; Serum; Signal Pathway; Signal Transduction; Testing; Ultrasonics; United States National Institutes of Health; Vertebral column; Water; axon growth; base; developmental neurotoxicity; dietary; disorder risk; gene environment interaction; human disease; human tissue; humanized mouse; in vivo; insight; male; morris water maze; mother nutrition; mouse model; neurodevelopment; neurotoxic; novel; object recognition; oxidation; pollutant; postnatal; pup; relating to nervous system; response; social; tool; vocalization

PROJECT SUMMARY/ABSTRACT Polychlorinated biphenyls (PCBs) remain a significant risk to human health, and a primary target of concern is the developing brain. Research on PCB developmental neurotoxicity (DNT) has focused almost exclusively on the higher chlorinated (HC)-PCBs; in contrast, our understanding of the potential for LC-PCBs to interfere with neurodevelopment is extremely limited. This is a troubling data gap in light of our discovery during the previous project period that the LC-PCBs 11 and 28 comprise >70% of the PCBs in the serum of pregnant women at increased risk for having a child with a neurodevelopmental disorder (NDD). We found that PCB 11 and its metabolites formed via cytochrome P450 (CYP)-mediated oxidation promote dendritic and axonal growth in vitro. These effects are observed at PCB 11 concentrations relevant to the human gestational environment, and the potency of the metabolites varied from that of the parent. Our preliminary data suggest that PCB 11 causes DNT via activation of CREB-dependent signaling pathways. Whether the metabolites alter neurodevelopment via the same molecular mechanism is not known. These findings, which were the first to identify the DNT potential of LC-PCBs, raise several critical questions that must be addressed to define the risk that LC-PCBs pose to the developing human brain: (1) Do LC-PCBs found in the gestational environment alter neurodevelopment in the intact brain? (2) What are the molecular mechanism(s) by which LC-PCBs alter neuronal morphogenesis? (3) Does human CYP-mediated metabolism activate LC-PCBs to developmental neurotoxicants? To address these questions, we will test the central hypothesis that CYP-mediated metabolism influences the in vivo effects of LC-PCBs on CREB-dependent neurodevelopmental processes. To test this novel hypothesis, we will leverage state-of-the-art mouse models engineered to express human CYP2A6 or CYP2B6 but not mouse Cyp2a, 2b, 2f2, 2g1, and 2s1 proteins (Cyp2abfgs-null mice). Focusing on LC-PCBs documented in the human gestational environment and developing brain, we will (a) identify the LC- PCB metabolites formed via human CYP2A6 and CYP2B6, and test their effects on CREB-dependent neurodevelopmental processes in primary neuron-glia co-cultures; and (b) determine how modulation of LC- PCB metabolism influences the dose-response relationship of LC-PCB DNT in vivo. The anticipated outcomes of these studies include the identification of LC-PCBs as a new class of environmental contaminants that interfere with neurodevelopment and novel mechanistic data regarding the role of CREB signaling and CYP- mediated bioactivation in PCB DNT. This research will impact public health not only by generating data critically needed to assess the risk LC-PCBs pose to the developing brain, but also by providing critical mechanistic insights regarding the plausibility of dietary and/or pharmacological manipulation of CYP activity to mitigate DNT risk in vulnerable subpopulations.

项目摘要/摘要 多氯联苯（PCB）仍然是人类健康的重大风险，而关注的主要目标是 发育中的大脑。 PCB发育神经毒性（DNT）的研究几乎完全关注 较高的氯化（HC）-PCB；相反，我们对LC-PCB的潜力的理解 神经发育非常有限。鉴于我们的发现，这是一个令人不安的数据差距 LC-PCB 11和28占孕妇血清中> 70％PCB的项目期间 患有神经发育障碍（NDD）的孩子的风险增加。我们发现PCB 11及其 通过细胞色素P450（CYP）介导的氧化形成的代谢产物促进树突状和轴突生长 体外。这些效果在与人类妊娠环境有关的PCB 11浓度下观察到 代谢物的效力与父母的效力不同。我们的初步数据表明PCB 11 通过激活CREB依赖性信号通路引起DNT。代谢物是否改变 通过相同的分子机制神经发育尚不清楚。这些发现，这是第一个 确定LC-PCB的DNT潜力，提出几个关键问题，必须解决以定义风险 LC-PCB构成了发展中的人脑：（1）在妊娠环境中发现的LC-PCB改变 完整大脑中的神经发育？ （2）LC-PCB改变的分子机制是什么 神经元形态发生？ （3）人CYP介导的代谢是否会激活LC-PCBS发育 神经毒性？为了解决这些问题，我们将测试CYP介导的中心假设 代谢影响LC-PCB对CREB依赖性神经发育过程的体内影响。到 检验这个新颖的假设，我们将利用设计用于表达人的最先进的鼠标模型 CYP2A6或CYP2B6而不是小鼠CYP2A，2B，2F2、2G1和2S1蛋白（CYP2ABFGS-NULL小鼠）。专注于 LC-PCB在人类的妊娠环境中记录了大脑，我们将（a）确定LC- 通过人CYP2A6和CYP2B6形成的PCB代谢产物，并测试其对CREB依赖性的影响 原发性神经元 - 培养物中的神经发育过程； （b）确定LC-的调节 PCB代谢影响体内LC-PCB DNT的剂量反应关系。预期的结果 其中的研究包括将LC-PCB鉴定为新的环境污染物， 干扰有关CREB信号传导和CYP-的作用的神经发育和新的机械数据 PCB DNT中介导的生物活化。这项研究不仅会通过生成数据影响公共卫生 评估LC-PCB对发展中的大脑的风险需要至关重要的需要，也可以通过提供关键 关于饮食和/或药理学操纵CYP活性的机械见解 减轻弱势亚群中的DNT风险。