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

项目摘要 今天，我们的社会面临着环境污染和迅速老龄化的健康负担的挑战。 人口全球寿命比100年前延长30年，五分之一的美国人将成为老年人 到2030年。考虑到这种长期的老化加上环境暴露，我们迫切需要 了解环境污染如何影响老年人的身体不同于年轻人的身体，以及 环境污染有助于老化表型。我们对化学品毒性的理解 来自于针对年轻人到中年人的人类研究，或者来自于针对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到环境污染物在老年人体内的毒性， 我们根本不明白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，因此遗传毒性剂被认为不太重要。 威胁现在，我们知道事实正好相反--大部分的大脑细胞，神经胶质细胞，都是有丝分裂的，在大脑中扮演着重要的角色 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的 非整倍体和染色体不稳定性与衰老和神经退行性疾病的早期。因此有 我们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）]是一个主要的环境健康问题，可以诱导衰老表型， 具有最明确的金属致染色体断裂机制。Cr（VI）也会导致脑损伤， 各种神经系统症状我们建议研究Cr（VI）在这种衰老模式中的作用，使用 青年、中年和老年大鼠通过饮水暴露于Cr（VI）90天。我们假设 动物将更容易受到Cr（VI）诱导的神经毒性，Cr（VI）通过以下方式诱导脑老化： 引起非整倍性和染色体不稳定性，导致神经胶质细胞衰老。我们将测试我们的假设 有两个目标。目的1将确定不同年龄的脑区和细胞群易受Cr（VI）毒性的影响。这 目的是使我们能够比较Cr（VI）的神经毒性在不同年龄和过早或晚期衰老的终点。 目的2：探讨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。 我们的研究将提供必要的详细见解铬（六）神经毒性，考虑年龄，性别，地区， 细胞类型特异性效应。我们的研究将进一步从机制上考虑遗传毒性如何有助于大脑 老化与在体内和体外技术。结果将提供关键和新颖的见解，了解铬（六）的 在衰老过程中的作用，识别大脑中的细胞和区域目标，以及老年大脑如何受到影响 不同的毒物。本研究还将为进一步研究神经毒性提供一个新的模型系统 以及Cr（VI）或其他金属的老化，并将有助于改善Cr（VI）风险评估， 由于缺乏这些数据，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.