Neurotoxicity due to Environmental complex Metal Mixtures Exposure

环境复杂金属混合物暴露引起的神经毒性

• 批准号: 10591120
• 负责人: Shyam Biswal
• 金额: $ 242.16万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591120
• 关键词: Adult; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Animal Model; Antioxidants; Anxiety; Biological; Biological Assay; Biological Markers; Brain; C57BL/6 Mouse; CRISPR/Cas technology; Chronic; Cognition; Data; Decision Making; Development; Dose; Electrophysiology (science); Environment; Environmental Exposure; Epidemiology; Epigenetic Process; Etiology; Exposure to; Foundations; Genes; Goals; Heavy Metals; Homeostasis; Human; Impaired cognition; Individual; Inflammation; Inflammatory; Knock-out; Knockout Mice; Knowledge; Life; Mediating; Memory; Metabolic; Metal exposure; Metals; Modeling; Mus; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neurologic; Neurologic Effect; Neurological outcome; Neurons; Neurotoxins; Organoids; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Pathway; Pathway interactions; Perinatal; Perinatal Exposure; Phenotype; Population; Predisposition; Risk; Risk Assessment; Risk Management; Role; Serum; Signal Transduction; Source; Synapses; Testing; Vulnerable Populations; adverse outcome; base; behavior test; chromium hexavalent ion; cytotoxic; design; drinking water; experimental study; exposed human population; gene environment interaction; impaired brain development; in vivo; insight; interest; metabolomics; metal complex; mouse model; nerve stem cell; nervous system disorder; nestin protein; neuroinflammation; neurotoxicity; novel; nuclear factor-erythroid 2; presynaptic; response; risk variant; sex; transcriptomics; treatment strategy

Abstract: Increasing evidence supports the role of metal exposures as a ubiquitous source of neurological diseases, including Alzheimer’s Disease (AD) and related dementia, in multiple populations worldwide. In real life, one is more likely to be exposed to metal/metalloid mixtures than individual metals. The US EPA has designated the ubiquitous combination of Pb, As, Cd, and Cr(VI) (PACC) as the top interaction profile of concern for exposure. However, there is still a critical knowledge gap on the adverse outcome pathways (AOPs) due to chronic exposure to mixtures of metals/metalloids, which hampers risk assessment of neurodegenerative diseases. The goal is to elucidate the mechanisms by which metal mixtures act in concert to elicit neurodegenerative AD effects to support the cumulative neurodegenerative disease risk assessment. Our preliminary data from in-vivo mouse experiments indicate that, unlike single metal exposures, chronic PACC mixture exposure during adulthood has sex-specific negative effects on cognition, memory, and anxiety. This correlated with increased serum neuronal decay biomarker (NFL-a), neuroinflammation, and imbalanced redox homeostasis due to altered Nrf2 signaling. In human brain organoids, the PACC mixture increased oxidative stress, while it reduced the expression of the pre-synaptic marker, Syn1, and the neuroprogenitor marker, Nestin, at different stages of organoid development. We hypothesize that interaction profile PACC metal mixtures relative to single metals at or below regulatory limit impairs brain development as well as accelerates cognitive decline, neurodegeneration, and eventually AD, due to epigenetic changes in interconnected inflammatory and oxidative stress pathways. We will test this using the following aims: SA 1: To determine the biological mechanisms by which exposure to PACC metal mixtures during adulthood cause AD-related neurocognitive decline. The cumulative risk of sex- and dose-specific neurotoxicity and neurodegeneration caused by adulthood exposures to individual metals vs. PACC mixtures will be determined using mouse models. The causality of oxidative stress and the Nrf2/KEAP1 pathway will be tested using Nrf2fl/fl or Keap1fl/fl knock-out mice. SA 2: To investigate the adverse neurological effects of perinatal exposure to PACC metal mixture at environmentally relevant doses. We will determine the neurological effects of PACC metal mixture in perinatally exposed adult mice and perform a cumulative risk assessment. SA 3: Determine potential gene x environment (G×E) interactions involved in PACC metal mixture-induced AD-related neurodegeneration. Using our CRISPR/Cas9 modified human organoids in which the AD risk gene APOEe4 is knocked out, we will study metal combinations at different stages of brain maturity, and investigate oxidative stress, transcriptomic and metabolic changes, and associated neurodegeneration. Impact: This study will provide insights into the long-term impact and causal mechanisms of metal mixture- induced neurotoxicity and help tailor risk management decisions to protect populations from metal-induced AD.

摘要：越来越多的证据支持金属暴露作为一种无处不在的神经学来源的作用 疾病，包括阿尔茨海默病(AD)和相关的痴呆症，在世界各地的多个人口中。在现实中 在生活中，一个人比单独的金属更有可能接触到金属/类金属混合物。美国环保局已经 将无处不在的铅、砷、镉和铬(VI)(PACC)组合指定为最受关注的交互配置文件 为了曝光。然而，由于以下原因，在不良结局途径(AOPS)方面仍存在严重的知识差距 长期接触金属/类金属混合物，这阻碍了对神经退行性变的风险评估 疾病。目的是阐明金属混合物协同作用的机制。 神经退行性AD效应支持神经退行性疾病的累积风险评估。我们的 小鼠体内实验的初步数据表明，与单一金属暴露不同，慢性PACC 成年期间接触混合物质会对认知、记忆和焦虑产生不同性别的负面影响。这 与血清神经元衰退生物标志物(NFL-a)升高、神经炎症和氧化还原失衡相关 由于Nrf2信号的改变而导致的动态平衡。在人脑有机化合物中，PACC混合物增加了氧化 应激，虽然它减少了突触前标记SYN1和神经前体标记Nestin的表达， 在有机体发育的不同阶段。我们假设PACC金属混合物的相互作用 相对于单一金属，达到或低于监管极限会损害大脑发育，并加速认知 衰退，神经变性，最终阿尔茨海默病，由于相互关联的炎症性和 氧化应激途径。我们将使用以下目标来测试这一点：SA 1：确定生物 成年期接触PACC金属混合物导致AD相关机制的研究 神经认知能力下降。性别和剂量相关的神经毒性和神经变性的累积风险 成年后暴露于单个金属与PACC混合物之间的关系将通过小鼠模型来确定。 氧化应激和Nrf2/Keap1途径的因果关系将使用Nrf2fl/fl或Keap1fl/f1基因敲除来检验 老鼠。SA 2：研究围产期接触PACC金属混合物对神经系统的不良影响 与环境有关的剂量。我们将测定PACC金属混合物的神经效应。 围产期暴露的成年小鼠，并进行累积风险评估。答案3：确定潜在基因x 环境(G×E)交互作用参与PACC金属混合物诱导的AD相关神经变性。 使用我们的CRISPR/Cas9修饰的人类器官，其中AD风险基因APOEe4被敲除，我们将 研究大脑成熟不同阶段的金属结合，并研究氧化应激、转录 和代谢变化，以及相关的神经退化。 影响：这项研究将为金属混合物的长期影响和原因机制提供见解- 诱导的神经毒性，并帮助定制风险管理决策，以保护人群免受金属诱导的AD的影响。