Disruption of transition metal homeostasis by Cd: Implications for aging

镉对过渡金属稳态的破坏：对衰老的影响

• 批准号: 8056614
• 负责人: CAROL A FIERKE
• 金额: $ 18.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-06 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056614
• 关键词: Aging; Aging-Related Process; Biological; Biological Assay; Biological Models; Cadmium; Carcinogens; Castor; Cell Line; Cell physiology; Cells; Chemistry; Complex; Copper; Coupled; Culture Media; DNA Damage; Data; Environment; Enzymes; Eukaryota; Fibroblasts; Fluorescence; Gene Silencing; Genes; Growth; Heavy Metals; Homeostasis; House mice; Human; Image; Industrial Product; Investigation; Ions; Iron; Kidney; Life; Light; Link; Longevity; Lung; Malignant neoplasm of lung; Malignant neoplasm of prostate; Malignant neoplasm of testis; Mammalian Cell; Mammals; Maps; Mass Spectrum Analysis; Measures; Metabolism; Metalloproteins; Metals; Molecular; Molecular Chaperones; Molecular and Cellular Biology; Organism; Oxidation-Reduction; Oxidative Stress; Peromyscus; Physiological; Plasma; Play; Production; Property; Proteins; RNA Interference; Rattus norvegicus; Reactive Oxygen Species; Renal carcinoma; Resistance; Rodent; Roentgen Rays; Role; Saccharomyces cerevisiae; Saccharomycetales; Series; Side; Skin; Source; Stream; Stress; Synchrotrons; System; Testing; Testis; Toxic effect; Transition Elements; Yeasts; Zinc; bone; cadmium-binding protein; cancer risk; carcinogenesis; cigarette smoking; cofactor; demineralization; fluorescence imaging; metal metabolism; novel; public health relevance; research study; response; toxic metal; uptake

DESCRIPTION (provided by applicant): Cadmium (Cd) is a toxic heavy metal found in the environment as a product of industrial contamination, and is classified as a human carcinogen. Cd is a significant contributor to the cancer risk associated with cigarette smoke, and has been linked to lung, renal, prostate and testicular cancer. Within cells, Cd toxicity results in DNA damage, and oxidative stress, including the production of reactive oxygen species (ROS); however, cadmium is not redox active under biological conditions and cannot directly catalyze ROS production. Data recently obtained using Saccharomyces cerevisiae indicates that a significant contributor to Cd toxicity is the disruption of copper (Cu) metabolism within the cell. Cu is an essential transition metal that serves as a catalytic cofactor in numerous enzymes, but is tightly regulated within cells and is toxic at high concentrations. Both Cu and Cd have also been linked to aging in mammals. Changes in Cu metabolism accompany the aging process, and increased Cd resistance correlates with increased species lifespan. One possible explanation for this correlation is that long-lived species have developed more efficient cellular metabolism for responding to increases in Cu and other transition metals associated with Cd toxicity. This hypothesis would be consistent with the results from S. cerevisiae. However, differences in the Cd response mechanisms preclude direct extrapolation of results obtained in yeast to more complex, mammalian systems. We therefore propose a directed series of experiments to test the potential for a mechanistic linkage between Cu metabolism in mammalian cells and Cd toxicity. Specifically, we aim to: (1) Examine the impact of Cd on transition metal homeostasis in mammalian fibroblast cells, by assaying changes in total metal content and by mapping the subcellular distributions of Cu and other transition metals in normal and Cd-exposed cells using synchrotron X-ray fluorescence microprobe imaging; (2) Analyze the involvement of specific transition metal transporters and chaperones in the origins of Cd toxicity using RNAi gene silencing and metal depletion experiments; and (3) Compare the metal content and distributions in untreated and Cd-treated fibroblasts derived from the skin of short-lived, Cd-sensitive and long-lived, Cd-tolerant rodents. Together, these experiments will establish if large-scale disruption of transition metal homeostasis contributes to the molecular origins of Cd toxicity in mammals, as it does in yeast, and shed light on differences in metal homeostasis associated with increased lifespan. PUBLIC HEALTH RELEVANCE: Cadmium (Cd) is a toxic metal ion, a human carcinogen and a major contributor to the cancer risk associated with cigarette smoke. In yeast, Cd toxicity is linked to disruption of copper (Cu) metabolism; however, it is unknown if the same is true in mammals. The experiments proposed here will establish whether disrupting the homeostasis of Cu or other transition metals contributes to Cd toxicity in mammals, and examine the possibility that differences in metal metabolism contribute to the Cd tolerance of long-lived species.

描述（由申请人提供）：镉（Cd）是一种在环境中发现的有毒重金属，是工业污染的产物，被归类为人类致癌物。镉是与吸烟相关的癌症风险的重要贡献者，并与肺癌，肾癌，前列腺癌和睾丸癌有关。在细胞内，镉毒性导致DNA损伤和氧化应激，包括活性氧（ROS）的产生;然而，镉在生物条件下没有氧化还原活性，不能直接催化ROS的产生。最近获得的数据使用酿酒酵母表明，镉毒性的一个重要贡献者是细胞内的铜（Cu）代谢的破坏。铜是一种重要的过渡金属，在许多酶中作为催化辅因子，但在细胞内受到严格调控，高浓度时有毒。铜和镉也与哺乳动物的衰老有关。Cu代谢的变化伴随着衰老过程，而Cd抗性的增加与物种寿命的增加相关。这种相关性的一个可能的解释是，长寿的物种已经开发出更有效的细胞代谢，以应对增加铜和其他过渡金属与镉毒性。这一假设与S.啤酒。然而，镉的反应机制的差异排除直接外推的结果在酵母中获得更复杂的，哺乳动物系统。因此，我们提出了一个有针对性的一系列实验，以测试在哺乳动物细胞中的铜代谢和镉毒性之间的机制联系的潜力。具体而言，我们的目标是：（1）检测镉对哺乳动物成纤维细胞中过渡金属稳态的影响，方法是测定总金属含量的变化，并使用同步加速器X射线荧光微探针成像绘制正常细胞和镉暴露细胞中铜和其他过渡金属的亚细胞分布图;（二）利用RNAi基因沉默和金属耗竭技术分析特定的过渡金属转运蛋白和分子伴侣在镉毒性起源中的作用实验;（3）比较短寿命、镉敏感和长寿命、镉耐受啮齿类动物皮肤成纤维细胞中未处理和镉处理的金属含量和分布。总之，这些实验将建立如果大规模的破坏过渡金属稳态有助于镉毒性的分子起源在哺乳动物中，因为它在酵母中，并阐明与寿命增加相关的金属稳态的差异。 公共卫生相关性：镉（Cd）是一种有毒的金属离子，是人类致癌物质，也是与香烟烟雾相关的癌症风险的主要贡献者。在酵母中，镉毒性与铜（Cu）代谢的破坏有关;然而，尚不清楚哺乳动物中是否也是如此。这里提出的实验将建立是否破坏铜或其他过渡金属的稳态有助于镉在哺乳动物中的毒性，并检查的可能性，在金属代谢的差异有助于镉耐受性的长寿物种。