Cr(VI)-Induced DNA Damage Contributes to Brain Aging

Cr(VI) 诱导的 DNA 损伤导致大脑衰老

• 批准号: 10287080
• 负责人: John Pierce Wise
• 金额: $ 23.41万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287080
• 关键词: Address; Affect; Age; Aging; American; Aneuploid Cells; Aneuploidy; Animal Model; Animals; Astrocytes; Attention; Biological Aging; Biological Models; Biological Process; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Brain Injuries; Brain region; Cell Aging; Cells; Cerebellum; Cerebrovascular system; Chemicals; Chromosomal Instability; Chronic; Cultured Cells; DNA Damage; DNA Double Strand Break; Data; Dementia; Double Strand Break Repair; Elderly; Endothelial Cells; Environment; Environmental Exposure; Environmental Health; Environmental Pollutants; Environmental Pollution; Etiology; Exhibits; Exposure to; Extravasation; Face; Functional disorder; Health; Heavy Metals; Hemorrhage; High Fat Diet; Hippocampus (Brain); Homeostasis; Human; Hypothalamic structure; Immunohistochemistry; In Vitro; Individual; Inductively Coupled Plasma Mass Spectrometry; Industrialization; Knowledge; Learning; Link; Literature; Longevity; Malignant Neoplasms; Memory impairment; Metabolic Diseases; Metals; Microglia; Mitotic; Motor Neuron Disease; Mutagens; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurologic Symptoms; Neurons; Onset of illness; Outcome; Pericytes; Phenotype; Play; Poison; Population; Premature aging syndrome; Process; Rattus; Reporting; Research; Risk; Risk Assessment; Risk Management; Rodent; Role; Route; Societies; Techniques; Testing; Tissues; Toxic Environmental Substances; Toxic effect; Toxicology; Vulnerable Populations; White Matter Disease; age group; age related; age related neurodegeneration; aged; aging brain; aging population; brain cell; brain health; cell type; chromium hexavalent ion; drinking water; gene environment interaction; genotoxicity; human disease; improved; in vivo; insight; lifestyle factors; metal poisoning; middle age; neurodegenerative phenotype; neuroinflammation; neuropathology; neurotoxic; neurotoxicity; neurovascular; neurovascular unit; novel; oxidative damage; premature; senescence; sex; toxicant

PROJECT SUMMARY Today our societies are challenged with the health burdens of environmental pollution and a rapidly aging population. Global lifespan is 30 years longer than it was 100 years ago, and 1 in 5 Americans will be geriatric by the year 2030. Given this prolonged aging combined with environmental exposures, we urgently need to understand how environmental pollution affects an aged body differently from a younger body and how environmental pollution contributes to aging phenotypes. Most of our understanding of toxic effects of chemicals come from human research focused on young to middle aged people or from animal studies using young to middle aged rodents. Very few studies have considered toxicity of environmental pollutants in an aged body or population and we simply do not understand the impacts on an aged population. Traditionally, the brain was considered composed of mostly post-mitotic neurons and hence genotoxic agents were considered less of a threat. Now, we know the opposite is true – most of the brain’s cells, the glia, are mitotic and play critical roles in protecting and supporting neuronal health. Recent studies show these glial cells can exhibit increased aneuploidy and chromosome instability with aging and early in neurodegenerative diseases. Hence, there is a critical need to understand how genotoxic chemicals affect brain health and contribute to premature aging. Hexavalent chromium [Cr(VI)] is a major environmental health concern that can induce aging phenotypes and has the best defined clastogenic mechanism of metals. Cr(VI) also causes brain damage that may be linked to a variety of neurological symptoms. We propose to investigate the role of Cr(VI) in this aging paradigm, using young vs middle-aged vs geriatric rats exposed to Cr(VI) for 90 days via drinking water. We hypothesize aged animals will be more susceptible to Cr(VI)-induced neurotoxicity and that Cr(VI)-induces brain aging by causing aneuploidy and chromosome instability resulting in glial senescence. We will test our hypothesis with two aims. Aim 1 will identify brain regions and cell populations vulnerable to Cr(VI) toxicity across ages. This aim will allow us to compare Cr(VI) neurotoxicity across ages and endpoints for premature or advanced aging. Aim 2 will determine the role of aneuploidy and chromosome instability in Cr(VI) neurotoxicity and brain aging. Our study will provide essential detailed insights into Cr(VI) neurotoxicity, considering age-, sex-, region-, and cell type-specific effects. Our study will further consider mechanistically how genotoxicity contributes to brain aging with in vivo and in vitro techniques. Outcomes will provide key and novel insights for understanding Cr(VI)’s role in the aging process, identifying cellular and regional targets in the brain, and how an aged brain is affected by toxicants differently. This study will also characterize a new model system for further study of neurotoxicity and aging for Cr(VI) or other metals, and will contribute to improvements in Cr(VI) risk assessment and management that are not currently possible because of limitations due to the absence of these data.

项目概要 今天，我们的社会面临着环境污染和快速老龄化带来的健康负担的挑战 人口。全球寿命比 100 年前延长了 30 年，五分之一的美国人将步入老年 到 2030 年。鉴于长期老化加上环境暴露，我们迫切需要 了解环境污染对老年人身体和年轻身体的影响有何不同，以及如何 环境污染导致衰老表型。我们对化学品毒性作用的大部分了解 来自针对年轻人到中年人的人类研究或使用年轻人到中年人的动物研究 中年啮齿动物。很少有研究考虑环境污染物对老年人或老年人的毒性。 我们根本不了解这对老年人口的影响。传统上，大脑是 被认为主要由有丝分裂后神经元组成，因此基因毒性剂被认为不太重要 威胁。现在，我们知道事实恰恰相反——大多数大脑细胞（神经胶质细胞）都进行有丝分裂并发挥着关键作用 保护和支持神经元健康。最近的研究表明这些神经胶质细胞可以表现出增加 衰老和神经退行性疾病早期的非整倍性和染色体不稳定。因此，有一个 迫切需要了解基因毒性化学物质如何影响大脑健康并导致过早衰老。 六价铬 [Cr(VI)] 是一个主要的环境健康问题，可诱发衰老表型和 具有最明确的金属断裂机制。 Cr(VI) 还会导致脑损伤，可能与以下因素有关： 各种神经症状。我们建议研究 Cr(VI) 在这种老化范式中的作用，使用 通过饮用水暴露于 Cr(VI) 90 天的年轻大鼠、中年大鼠和老年大鼠。我们假设年龄 动物更容易受到 Cr(VI) 诱导的神经毒性的影响，并且 Cr(VI) 会通过以下方式诱导大脑老化： 引起非整倍体和染色体不稳定，导致神经胶质衰老。我们将检验我们的假设 有两个目标。目标 1 将确定各个年龄段易受 Cr(VI) 毒性影响的大脑区域和细胞群。这 目标将使我们能够比较不同年龄和早衰或晚期衰老终点的 Cr(VI) 神经毒性。 目标 2 将确定非整倍性和染色体不稳定性在 Cr(VI) 神经毒性和脑衰老中的作用。 我们的研究将提供有关 Cr(VI) 神经毒性的重要详细见解，考虑年龄、性别、地区和 细胞类型特异性效应。我们的研究将进一步从机制上考虑基因毒性如何影响大脑 体内和体外技术的老化。结果将为理解 Cr(VI) 提供关键且新颖的见解 在衰老过程中的作用，识别大脑中的细胞和区域目标，以及衰老的大脑如何受到影响 毒物的作用不同。这项研究还将表征一个新的模型系统，用于进一步研究神经毒性 Cr(VI) 或其他金属的老化和老化，并将有助于改进 Cr(VI) 风险评估和 由于缺乏这些数据而造成的限制，目前无法进行管理。