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: 10369814
• 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/10369814
• 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; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Genomics; Geography; Goals; Hippocampus (Brain); 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; Research; Research Design; Resolution; Risk; Risk Factors; Socioeconomic Status; Specificity; Strategic Planning; Testing; Time; Tissues; Toxicant exposure; Toxicology; Translations; advanced disease; base; 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; socioeconomic disparity; symposium; toxicant; transcriptome sequencing; transcriptomics

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.

项目摘要 阿尔茨海默氏病和相关痴呆症的终身风险和人口伯宁很高。许多痴呆症 来自环境因素的风险贡献的特征很差。在纵向流行病学研究中 铅（PB）暴露与认知能力下降和阿尔茨海默氏病有关。尽管努力了公共卫生，但PB 全球范围内的风险仍然很广泛，并具有大量的曝光分布。早期生活特别 脆弱的暴露期。使用已建立的围产期PB暴露的鼠标模型，来自我们的数据 研究小组建议，通过表观遗传机制，PB暴露持续到成年后的影响，尽管 随着时间的推移，大脑区域内的表观遗传效应尚未被映射。大脑区域特异性分析 围产期PB跨多个表观基因组的全基因组度量是至关重要的。在 此外，使用单细胞RNA - 测序，我们的初步数据证明了脑细胞类型具有可变 对围产期PB暴露的敏感性，特别是神经胶质细胞。 PB跨PB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PB暴露的细胞。我们还显示了Pb基因 小鼠中的靶标与关键的人类痴呆途径重叠。将毒理学进一步翻译成 流行病学发现对于最大程度地提高了这两种研究设计的优势至关重要。在一起，我们的初步 数据支持大脑区域和细胞类型的表观遗传重编程和基因表达的特异性变化 大脑中PB暴露的目标可能是对人类相关途径的作用，并强调我们团队的 该领域的生产力和专业知识。我们研究的长期目标是了解特定的性别 在大脑组成和人类痴呆发育的纵向PB暴露中。 研究小鼠周围暴露于PB或对照饮食的研究，我们将多次测试PB脑差异 指向长达18个月。我们将1）测试围产期PB暴露的影响如何持续到成年 测定病理变化，行为，RNA表达，DNA甲基化和 在三个时间点上，三个大脑区域之间的染色质构象。我们将2）确定细胞类型 使用病理学和最先进的超高分辨率单细胞最容易受到PB影响的大脑 空间转录组学。我们将3）将围产期PB暴露于现有的小鼠中的分子作用联系起来 有关人神经退行性疾病的数据。这将是跨多个脑细胞类型的第一个特定图表 响应毒物暴露的表观基因组水平。使用PB作为毒剂模型来鉴定分子 围产期暴露对脑区域和脑细胞类型的影响，我们将发现机械洞察力 环境暴露如何通过重要毒理学，发育生物学和 公共卫生的影响。