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.

项目概要 多氯联苯 (PCB) 仍然对人类健康构成重大风险，主要关注目标是 正在发育的大脑。流行病学研究报告了发育之间的正相关关系 接触 PCB 会增加神经发育障碍 (NDD) 的风险；然而，实验研究 旨在评估这些关联的强度并确定 PCB DNT 的生物学机制 几乎完全专注于高氯化 (HC)-PCB，这是在 传统的商业 PCB 混合物。相比之下，有关低氯化 (LC)-PCB 的潜力的数据 对神经发育的干扰极为有限。考虑到最近的报告，这是一个令人不安的差距 LC-PCB 的环境水平在全球范围内不断增加，并且 LC-PCB 同系物 11 和 28 研究发现，孕妇血清中 PCB 含量超过 70%，生出患有该病的孩子的风险增加 ND。我们之前报道过 PCB 11 及其代谢物通过细胞色素 P450 (CYP) 介导形成 氧化促进了体外树突和轴突的生长，并且在一定浓度下观察到了这些效应 与人类妊娠环境有关。有趣的是，代谢物的效力与 家长。我们的体外研究还表明 PCB 11 通过激活 CREB-增强树突生长 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。我们还知道 (1) 在人体组织中发现的其他 LC-PCB 是否含有 DNT 活动; (2) LC-PCB 或其代谢物调节已知受到调节的其他神经发育结果 通过 CREB ​​依赖性信号传导，特别是轴突生长和神经元凋亡；或 (3) 的贡献 细胞色素 P450 介导的 LC-PCB DNT 代谢。我的中心假设是 LC-PCB 及其 人类 CYP2A6 和 CYP2B6 形成的代谢物通过以下方式改变初级神经元的神经发育： CREB ​​依赖机制。为了验证这一假设，我将描述以下物质的体外 DNT 特征： 与人体相关的 LC-PCB 及其代谢物，评估特定人体对 LC-PCB 的代谢情况 CYPs影响DNT，并评估CREB在LC-PCB DNT中的作用。这项研究将产生数据 迫切需要为 LC-PCB 对人体产生神经毒性作用的可能性进行风险评估。 正在发育的大脑。这些研究的数据还将提供有关 CREB ​​作用的新机制见解 和 LC-PCB DNT 中的 CYPS。鉴于 CREB ​​功能获得性突变与 NDD 的关联，以及 人类 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 LC-PCB DNT 会提出有关影响 NDD 的基因-环境相互作用的可检验假设 风险以及减少高危人群中 LC-PCB DNT 的可能饮食和/或药物策略。