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。流行病学研究报告了发展之间的正相关 暴露于PCB并增加神经发育障碍的风险（NDD）；但是，实验研究 旨在评估这些关联的强度并确定PCB DNT的生物学机制 几乎专注于较高的氯化（HC）-PCB， 旧版商业PCB混合物。相反，有关下氯化（LC）-PCB的潜力的数据 干扰神经发育非常有限。考虑到最近的报道，这是一个令人不安的差距 LC-PCB的环境水平在全球范围内增加，LC-PCB同类物11和28是 发现在孕妇的血清中占> 70％的PCB，患有孩子的风险增加 NDD。我们先前报道了PCB 11及其代谢物是通过细胞色素P450（CYP）介导的 氧化促进了体外树突状和轴突生长，在浓度下观察到这些作用 与人类妊娠环境有关。有趣的是，代谢物的效力与 父母。我们的体外研究还表明，PCB 11通过激活Creb-增强了树突状的生长 依赖性信号通路，但是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是否具有DNT 活动; （2）LC-PCB或其代谢物调节已知受调节的其他神经发育结果 通过依赖CREB的信号传导，特别是轴突生长和神经元凋亡；或（3） 细胞色素P450介导的代谢对LC-PCB DNT。我的中心假设是LC-PCB及其 通过人CYP2A6和CYP2B6形成的代谢产物通过原代神经元的神经发育而形成 CREB依赖机制。为了检验这一假设，我将表征 与人相关的LC-PCB及其代谢产物，评估特定人类的LC-PCB代谢如何 CYP会影响DNT，并评估CREB在LC-PCB DNT中的作用。这项研究将生成数据 至关重要的是，要评估LC-PCB对神经毒性影响的潜力的风险评估。 发展大脑。这些研究的数据还将提供有关CREB作用的新机械见解 LC-PCB DNT中的CYP。鉴于CREB中功能障碍突变与NDD的关联， 人CYP中众所周知的功能多态性，涉及CREB和/或CYP介导的代谢的数据 在LC-PCB中，DNT将提出有关影响NDD的基因环境相互作用的可检验的假设 风险和可能的饮食和/或药理学策略，以减少高危人群中的LC-PCB DNT。