Investigating the cellular and molecular mechanisms of lower-chlorinated polychlorinated biphenyl developmental neurotoxicity

研究低氯多氯联苯发育神经毒性的细胞和分子机制

• 批准号: 10678135
• 负责人: Jessie Renee Badley
• 金额: $ 4.03万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678135
• 关键词: 7alpha hydroxylase; Address; Air; Animal Model; Animals; Arizona; Biological; Biological Assay; Blood; Brain; CYP2B6 gene; Child; Chlorine; Coculture Techniques; Cyclic AMP-Responsive DNA-Binding Protein; Cytochrome P450; Data; Development; Environment; Exposure to; Food; Funding; Genetic Polymorphism; Growth; Health; Heritability; High Risk Woman; Hippocampus; Human; Human Milk; Hydroxyl Radical; In Vitro; Industrialization; Iowa; Mediating; Metabolism; Molecular; Molecular Target; Morphogenesis; Mus; National Institute of Environmental Health Sciences; Neonatal; Neurodevelopmental Disorder; Neuroglia; Neurons; Neurotoxins; Outcome; Parents; Polychlorinated Biphenyls; Populations at Risk; Predisposition; Pregnancy; Pregnant Women; Process; Production; Reporting; Research; Research Design; Risk; Risk Assessment; Rodent; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Signaling Protein; Small Interfering RNA; Sulfate; Testing; Universities; Water; axon growth; developmental neurotoxicity; dietary; diphenyl; disorder risk; epidemiology study; experimental study; gain of function mutation; gene environment interaction; human tissue; insight; knock-down; neonatal mice; neurodevelopment; neuron apoptosis; neuropsychiatry; neurotoxic; novel; oxidation; pharmacologic

PROJECT SUMMARY Polychlorinated biphenyls (PCBs) remain a significant risk to human health, and a primary target of concern is the developing brain. Epidemiological studies have reported positive associations between developmental exposures to PCBs and increased risk for neurodevelopmental disorders (NDD); however, experimental studies designed to assess the strength of these associations and identify biological mechanisms underlying PCB DNT have focused almost exclusively on the higher chlorinated (HC)-PCBs, the predominant congeners found in the legacy commercial PCB mixtures. In contrast, data regarding the potential for lower chlorinated (LC)-PCBs to interfere with neurodevelopment is extremely limited. This is a troubling gap considering recent reports that environmental levels of LC-PCBs are increasing worldwide and that the LC-PCB congeners 11 and 28 were found to comprise >70% of PCBs in the serum of pregnant women at increased risk for having a child with an NDD. We previously reported that PCB 11 and its metabolites formed via cytochrome P450 (CYP)-mediated oxidation promoted dendritic and axonal growth in vitro, and these effects were observed at concentrations relevant to the human gestational environment. Interestingly, the potency of the metabolites varied from that of the parent. Our in vitro studies also suggested that PCB 11 enhanced dendritic growth via activation of CREB- dependent signaling pathways, but whether the metabolites alter neurodevelopment via the same molecular mechanism is not known. We also do we know whether (1) other LC-PCBs found in human tissues have DNT activity; (2) LC-PCBs or their metabolites modulate other neurodevelopmental outcomes known to be regulated by CREB-dependent signaling, specifically axonal growth and neuronal apoptosis; or (3) the contribution of cytochrome P450-mediated metabolism to LC-PCB DNT. My central hypothesis is that LC-PCBs and their metabolites formed via human CYP2A6 and CYP2B6 alter neurodevelopment in primary neurons via CREB-dependent mechanisms. To test this hypothesis, I will be characterizing the in vitro DNT profile of human-relevant LC-PCBs and their metabolites, assessing how the metabolism of LC-PCBs by specific human CYPs influences DNT, and evaluating the role of CREB in LC-PCB DNT. This research will generate data critically needed to inform risk assessments of the potential for LC-PCBs to exert neurotoxic effects on the developing brain. Data from these studies will also provide novel mechanistic insights regarding the role of CREB and CYPS in LC-PCB DNT. Given the association of gain-of-function mutations in CREB with NDDs, and the well-known functional polymorphisms in human CYPs, data implicating CREB and/or CYP-mediated metabolism in LC-PCB DNT would suggest testable hypotheses regarding gene-environment interactions that influence NDD risk and possible dietary and/or pharmacological strategies for reducing LC-PCB DNT in at-risk populations.

项目总结 多氯联苯(多氯联苯)仍然对人类健康构成重大威胁，令人担忧的主要目标是 发育中的大脑。流行病学研究报告称，发育迟缓之间存在正相关 暴露于多氯联苯和增加神经发育障碍(NDD)的风险；然而，实验研究 旨在评估这些关联的强度并确定多氯联苯DNT的生物学机制 几乎完全集中在较高的氯化(HC)-多氯联苯，在 传统商业印刷电路板混合物。相比之下，有关较低氯化(LC)-多氯联苯的潜力的数据 对神经发育的干预极其有限。考虑到最近的报道，这是一个令人不安的差距 世界各地的液晶多氯联苯的环境水平正在上升，液晶多氯联苯的同系物11和28是 发现在怀孕风险增加的孕妇血清中含有70%的多氯联苯 NDD。我们先前报道了PCB11及其代谢产物是通过细胞色素P450(CYP)介导形成的 氧化在体外促进树突状细胞和轴突的生长，并在浓度下观察到这些影响。 与人类的孕育环境有关。有趣的是，这些代谢物的效力与 家长。我们的体外研究还表明，PCB11通过激活CREB-1促进树突状细胞的生长。 依赖的信号通路，但代谢物是否通过相同的分子改变神经发育 机制尚不清楚。我们也知道(1)在人体组织中发现的其他LC-PCB是否含有DNT 活性；(2)LC-多氯联苯或其代谢物调节其他已知受调节的神经发育结果 通过CREB依赖的信号，特别是轴突生长和神经元凋亡；或(3) 细胞色素P450介导的LC-PCBDNT代谢。我的中心假设是液晶多氯联苯及其 人细胞色素P450 2A6和细胞色素P450 2 B6形成的代谢产物通过 CREB依赖的机制。为了验证这一假设，我将描述DNT的体外图谱 人类相关的LC-PCbs及其代谢物，评估特定人类对LC-PCbs的代谢 Cyps对DNT的影响，以及CREB在LC-PCBDNT中的作用。这项研究将产生数据 迫切需要提供信息，以评估LC-多氯联苯对 发育中的大脑。这些研究的数据还将为CREB的作用提供新的机制见解 和Cyps在LC-PCBDNT中。考虑到CREB的功能增益突变与NDDS的关联，以及 已知的人类细胞色素P450功能多态，CREB和/或CYP介导的代谢数据 在LC-PCB中，DNT将提出关于影响NDD的基因-环境相互作用的可检验假说 在高危人群中减少LC-PCBDNT的风险和可能的饮食和/或药物策略。