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

项目摘要 阿尔茨海默病和相关痴呆症的终生风险和人口负担很高。许多痴呆症 环境因素的风险贡献特征不明显。在纵向流行病学研究中， 铅暴露与认知能力下降和阿尔茨海默病有关。尽管公共卫生努力， 在世界范围内，接触仍然很普遍，但接触差异很大。早期生活是一个特别 脆弱的暴露期。使用已建立的围产期铅暴露小鼠模型， 尽管如此，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还没有被绘制出来。脑区特异性分析 迫切需要通过围产期铅在表观基因组的多个水平上进行全基因组测量。在 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的 围产期铅暴露的易感性，特别是神经胶质细胞。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。我们还显示了Pb基因 小鼠中的靶点与人类痴呆症的关键通路重叠。毒理学的进一步翻译 流行病学调查结果对于最大限度地发挥两种研究设计的优势至关重要。我们初步的 数据支持表观遗传重编程和基因表达中的脑区域和细胞类型特异性改变 作为铅暴露在大脑中的可能目标，作用于人类相关通路，并强调我们团队的 在这方面的生产力和专业知识。我们研究的长期目标是了解性别特异性 围产期铅暴露对脑成分和人类痴呆发展的影响沿纵向 研究小鼠围产期暴露于铅或对照饮食，我们将测试铅脑差异在多个时间 最多18个月。我们将1）测试围产期铅暴露的影响如何持续到成年期， 分析病理变化、行为、RNA表达、DNA甲基化、DNA羟甲基化，以及 在三个时间点跨越三个脑区域的染色质构象。我们将确定细胞类型， 大脑最容易受到铅的影响，使用病理学和最先进的单细胞 空间转录组学我们将3）将围产期铅暴露对小鼠的分子效应与现有的 人类神经退行性疾病的数据。这将是第一个跨多个脑细胞类型的特定地图 表观基因组水平的变化。以铅为模式毒物， 围产期暴露对大脑区域和脑细胞类型的影响，我们将发现对 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。

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.