Risk of Alzheimer's Disease and Related Dementias from Perinatal Lead Exposure: Brain Region and Cell Type Effects

围产期铅暴露导致阿尔茨海默病和相关痴呆的风险：大脑区域和细胞类型的影响

• 批准号: 10570921
• 负责人: Kelly Marie Bakulski
• 金额: $ 73.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570921
• 关键词: Adult; Affect; Age; Age Months; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Area; Autopsy; Behavior; Biological; Biological Assay; Biology; Blood; Brain; Brain Pathology; Brain region; Cells; Cerebellum; Chromatin; Complex; DNA; DNA Methylation; Data; Dementia; Development; Developmental Biology; Disease; Elderly; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epigenetic Process; Ethnic Origin; Evaluation; Exposure disparity; Exposure to; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Genomics; Geography; Goals; Hippocampus; Human; Impaired cognition; Incidence; Intervention; Lead; Life; Link; Longitudinal Studies; Maps; Measures; Methods; Modeling; Molecular; Molecular Conformation; Mus; National Institute on Aging; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Pathologic; Pathology; Pathway interactions; Pattern; Perinatal; Perinatal Exposure; Population; Predisposition; Prevention; Productivity; Public Health; Race; Recommendation; Research; Research Design; Risk; Risk Factors; Socioeconomic Status; Specificity; Strategic Planning; Testing; Time; Tissues; Toxicant exposure; Toxicology; Translations; advanced disease; brain cell; brain morphology; cell type; dietary control; disorder prevention; early life exposure; emerging adult; epidemiology study; epigenome; experimental study; genetic risk factor; genome-wide analysis; in vivo; insight; lead exposure; lifetime risk; modifiable risk; mouse model; neurotoxicology; novel; prevent; response; sex; single-cell RNA sequencing; symposium; toxicant; transcriptome sequencing; transcriptomics; ultra high resolution

PROJECT SUMMARY The lifetime risk and population burden of Alzheimer’s disease and related dementias is high. Many dementias have a poorly characterized risk contribution from environmental factors. In longitudinal epidemiology studies, lead (Pb) exposure is linked to cognitive decline and Alzheimer’s disease. Despite public health efforts, Pb exposure remains widespread worldwide, with substantial exposure disparities. Early life is a particularly vulnerable exposure period. Using an established mouse model of perinatal Pb exposure, data from our research team suggests effects of Pb exposure persist into adulthood through epigenetic mechanisms, though epigenetic effects within brain regions over time have not been mapped. Brain region-specific analyses of genome-wide measures across multiple levels of the epigenome by perinatal Pb are critically needed. In addition, using single cell RNA-sequencing, our preliminary data demonstrate brain cell types have variable susceptibility to perinatal Pb exposure, specifically glial cells. Cell type-specific analyses of Pb exposure across time and brain region will establish cells particularly vulnerable to Pb exposure. We also showed Pb gene targets in the mouse overlap with key human dementia pathways. Further translation of toxicology to epidemiology findings is essential to maximize the advantages of both study designs. Together, our preliminary data support brain region and cell type specific alterations in epigenetic reprogramming and gene expression as likely targets of Pb exposure in the brain, which act on human relevant pathways, and highlight our team’s productivity and expertise in this area. The long-term goal of our research is to understand the sex-specific impacts of perinatal Pb exposure on brain composition and human dementia development. In a longitudinal study of mice perinatally exposed to Pb or control diet, we will test for Pb brain differences at multiple time points up to 18-months. We will 1) test how the effects of perinatal Pb exposure persist into adulthood by assaying pathological changes, behavior, RNA expression, DNA methylation, DNA hydroxymethylation, and chromatin conformation across three brain regions at three time points. We will 2) determine cell types in the brain most susceptible to the effects of Pb, using pathology and state-of-the-art ultrahigh resolution single cell spatial transcriptomics. We will 3) relate the molecular effects in mice from perinatal Pb exposure to existing data on human neurodegenerative disorders. This will be the first brain cell type specific map across multiple levels of the epigenome in response to a toxicant exposure. Using Pb as a model toxicant to identify molecular effects of perinatal exposure on brain regions and brain cell types, we will discover mechanistic insights into how environmental exposures drive dementia incidence with important toxicology, developmental biology, and public health implications.

项目概要 阿尔茨海默病和相关痴呆症的终生风险和人口负担很高。 在纵向流行病学研究中，环境因素的风险贡献特征不明确。 尽管公共卫生部门做出了努力，但铅 (Pb) 暴露与认知能力下降和阿尔茨海默病有关。 暴露在世界范围内仍然很普遍，尤其是早期生活中的暴露差异很大。 使用已建立的围产期铅暴露小鼠模型，数据来自我们的数据。 研究小组认为，铅暴露的影响通过表观遗传机制持续到成年期 随着时间的推移，大脑区域内的表观遗传效应尚未被绘制出来。 迫切需要通过围产期 Pb 对表观基因组的多个水平进行全基因组测量。 此外，使用单细胞 RNA 测序，我们的初步数据表明脑细胞类型具有可变性 对围产期铅暴露的敏感性，特别是神经胶质细胞对铅暴露的细胞类型特异性分析。 时间和大脑区域将建立特别容易受到铅暴露的细胞。我们还展示了铅基因。 小鼠中的靶点与人类痴呆的关键途径重叠。毒理学的进一步转化。 流行病学研究结果对于最大限度地发挥我们的初步研究设计的优势至关重要。 数据支持表观遗传重编程和基因表达的大脑区域和细胞类型特异性改变 作为大脑中铅暴露的可能目标，它作用于人类相关通路，并强调了我们团队的 我们研究的长期目标是了解特定性别的生产力和专业知识。 围产期铅暴露对大脑成分和人类痴呆症发展的纵向影响。 对围产期暴露于 Pb 或对照饮食的小鼠进行研究，我们将多次测试 Pb 大脑差异 我们将 1) 测试围产期铅暴露的影响如何持续到成年期。 检测病理变化、行为、RNA 表达、DNA 甲基化、DNA 羟甲基化和 我们将 2) 确定三个时间点的三个大脑区域的染色质构象。 利用病理学和最先进的超高分辨率单细胞研究大脑最容易受到铅的影响 我们将 3) 将围产期铅暴露对小鼠的分子影响与现有的铅暴露联系起来。 关于人类神经退行性疾病的数据，这将是第一个跨多种脑细胞类型的特定图谱。 使用铅作为模型毒物来识别分子毒物的表观基因组水平。 围产期暴露对大脑区域和脑细胞类型的影响，我们将发现以下机制的见解 环境暴露如何通过重要的毒理学、发育生物学和 公共卫生影响。