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

项目总结 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岁，每5个美国人中就有1人是老年人 到2030年。考虑到这种长期的老龄化和环境暴露，我们迫切需要 了解环境污染对老年人的影响与对年轻人的影响不同，以及如何 环境污染导致表型老化。我们对化学物质的毒性作用的大部分了解 来自以年轻人和中年人为重点的人类研究，或来自使用年轻人和 中年啮齿动物。很少有研究考虑环境污染物对老年人的毒性或 我们根本不了解这对老龄人口的影响。传统上，大脑是 被认为主要由有丝分裂后神经元组成，因此遗传毒性药物被认为是较少的 威胁。现在，我们知道事实恰恰相反--大脑的大多数细胞--神经胶质细胞--都是有丝分裂的，并发挥着关键作用 在保护和支持神经元健康方面。最近的研究表明，这些神经胶质细胞可以表现出 神经退行性疾病的非整倍体和染色体不稳定与增龄和早期。因此，有一个 迫切需要了解遗传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)]是一种主要的环境健康问题，可导致衰老表型和 具有最明确的金属碎裂机制。铬(VI)也会导致脑损伤，这可能与 各种神经症状。我们建议研究铬(VI)在这种衰老范式中的作用，使用 幼年、中年和老年大鼠饮水染毒90d。我们假设上了年纪 动物将更容易受到铬(VI)诱导的神经毒性，并且铬(VI)通过以下方式诱导大脑衰老 导致非整倍体和染色体不稳定，导致神经胶质细胞衰老。我们将检验我们的假设 有两个目标。目标1将确定不同年龄段易受铬(VI)毒性影响的脑区和细胞群。这 AIM将使我们能够比较铬(VI)在不同年龄和过早或晚期衰老终点的神经毒性。 目的2研究非整倍体和染色体不稳定性在铬(VI)神经毒性和脑老化中的作用。 我们的研究将为铬(VI)的神经毒性提供必要的详细见解，考虑到年龄、性别、地区和 特定于细胞类型的效果。我们的研究将进一步从机制上考虑遗传毒性对大脑的影响。 利用体内和体外技术进行衰老。研究结果将为理解铬(VI)的S提供关键和新颖的见解 在衰老过程中的作用，识别大脑中的细胞和区域靶点，以及衰老的大脑是如何受到影响的 不同的毒物造成的。这项研究还将表征一种新的模型系统，用于进一步研究神经毒性 以及对铬(VI)或其他金属的老化，并将有助于改进铬(VI)风险评估和 由于缺乏这些数据而受到限制，目前无法进行管理。

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.