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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos 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

项目摘要

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神经系统疾病普遍来源的作用。事实上，全球多个人群都患有阿尔茨海默病 (AD) 和相关痴呆症。在生活中，人们比单一金属更有可能接触金属/类金属混合物。将普遍存在的 Pb、As、Cd 和 Cr(VI) (PACC) 组合指定为最受关注的相互作用特征然而，由于不良后果途径（AOP），仍然存在严重的知识差距。长期接触金属/类金属混合物，这妨碍了神经退行性疾病的风险评估目标是阐明金属混合物协同作用引发疾病的机制。神经退行性 AD 效应支持我们的累积神经退行性疾病风险评估。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会对认知、记忆和焦虑产生特定性别的负面影响。与血清神经元衰变生物标志物 (NFL-a) 增加、神经炎症和氧化还原失衡相关由于 Nrf2 信号改变导致的稳态，PACC 混合物增加了人脑类器官的氧化。压力，同时它减少了突触前标记 Syn1 和神经祖细胞标记 Nestin 的表达，我们捕获了 PACC 金属混合物在类器官发育的不同阶段的相互作用特征。相对于单一金属，达到或低于监管限值会损害大脑发育并加速认知能力由于相互关联的炎症和疾病的表观遗传变化，导致神经衰弱、神经退行性变，最终导致 AD。我们将使用以下目标对此进行测试： SA 1：确定生物途径。成年期间接触 PACC 金属混合物导致 AD 相关的机制神经认知能力下降。性别和剂量特异性神经毒性和神经变性的累积风险。将使用小鼠模型来确定成年期接触单个金属与 PACC 混合物所引起的差异。将使用 Nrf2fl/fl 或 Keap1fl/fl 敲除来测试氧化应激和 Nrf2/KEAP1 通路的因果关系 SA 2：研究围产期暴露于 PACC 金属混合物的不良神经学影响。我们将确定 PACC 金属混合物在环境相关剂量下的神经学影响。围产期暴露的成年小鼠并进行累积风险评估 SA 3：确定潜在基因 x。环境（G×E）相互作用参与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组合，并研究氧化应激、转录组学和代谢变化以及相关的神经变性。影响：这项研究将深入了解金属混合物的长期影响和因果机制诱导的神经毒性，并帮助制定风险管理决策，以保护人群免受金属诱导的 AD。