Nickel and toxic topoisomerase I products
镍和有毒拓扑异构酶 I 产品
基本信息
- 批准号:10374135
- 负责人:
- 金额:$ 35.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-18 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAlloysAneuploidyAnimalsBRCA1 geneBiochemicalBiological AssayCancerousCarcinogensCell SurvivalCellsChemicalsChromosomal RearrangementChromosome abnormalityChromosomesComplexCultured CellsDNADNA DamageDNA Double Strand BreakDNA RepairDNA Sequence AlterationDNA replication forkDNA-protein crosslinkDefectDependenceDoseDouble Strand Break RepairEnvironmentEnvironmental PollutionEnzymesEventExposure toFiberFossil FuelsGeneticGenetic RecombinationGenomicsHumanIncinerationIndividualIndustrializationInhalationIonsLigationLinkLungLymphocyteMalignant NeoplasmsMalignant neoplasm of lungMeasurementMetalsMethodologyMicrotubulesMitotic spindleModelingMolecularMolecular AbnormalityMutationNickelNonhomologous DNA End JoiningNoseOccupational ExposureOncogenicPopulationProcessProductionRisk AssessmentRoleRotationS phaseSourceStainless SteelSuperhelical DNATestingTimeTumorigenicityType I DNA TopoisomerasesWorkanimal tissuebasecancer riskcarcinogenicitycell transformationcostdesigndietaryexposed human populationgenotoxicityhomologous recombinationimprovedlung developmentnovelnovel markernucleasepollutantpreventrecombinational repairrepairedsingle moleculesuperfund sitewasting
项目摘要
Project Summary
Nickel (Ni) is a major industrial metal and a common environmental contaminant that is firmly
established as a human carcinogen. Inhalation of Ni compounds in occupationally exposed populations
has been found to cause lung and nasal cancers. Tumorigenicity of different forms of Ni was linked to
the intracellular presence of Ni(II) ions. Mechanisms of carcinogenic activity of Ni are poorly understood,
as Ni compounds were weak or negative in the standard mutagenicity assays and Ni(II) ions do not
react with DNA. Consequently, Ni is commonly described as a nongenotoxic carcinogen. However, Ni-
treated cultured cells and lymphocytes from Ni-exposed workers have consistently shown the presence
of chromosomal rearrangements that typically originate from DNA double-strand breaks (DSBs). Also
contradicting its nongenotoxic description is the ability of Ni(II) to cause covalent DNA-protein crosslinks
(DPCs) in experimental animals and in occupationally exposed individuals. The presence of
chromosomal abnormalities and DPCs despite the apparent lack of mutagenicity and DNA reactivity
suggests that Ni may engage some unusual genotoxicity mechanisms. Based on extensive preliminary
results, this project is designed to investigate a novel hypothesis that Ni(II) causes DSBs, DPCs, and
cell transformation by inducing genotoxic topoisomerase I-DNA products. The proposed studies will
determine (1) mechanisms of Ni(II)-induced defects in homologous recombination repair of DSBs, (2)
the importance of error-prone DSB repair in the production of oncogenic genetic changes by Ni(II), and
(3) formation and pathophysiological significance of Ni-induced topoisomerase I-containing DPCs and
DNA breaks. The completion of this work is expected to uncover molecular mechanisms of the
formation of oncogenic genetic abnormalities by a nonmutagenic carcinogen Ni and identify novel
biomarkers of DNA damage by this metal.
项目摘要
镍(Ni)是一种主要的工业金属,也是一种常见的环境污染物
被确认为人类致癌物质。职业性接触人群吸入镍化合物的研究
已被发现会导致肺癌和鼻癌。不同形态镍的致瘤性与
细胞内Ni(II)离子的存在。镍的致癌活性机制还知之甚少,
因为镍化合物在标准的致突变性检测中是弱的或阴性的,而镍(II)离子不是
与DNA发生反应。因此,镍通常被描述为一种非遗传毒性致癌物。然而,倪妮-
来自镍接触工人的经过处理的培养细胞和淋巴细胞一直显示出
通常源于DNA双链断裂(DSB)的染色体重排。也是
与其非遗传毒性描述相矛盾的是,镍(II)能够引起共价DNA-蛋白质交联键
(DPC)在实验动物和职业暴露的个人中。.的存在
染色体异常和DPC,尽管明显缺乏突变性和DNA反应性
提示镍可能参与了一些不寻常的遗传毒性机制。基于广泛的初步调查
结果:本项目旨在研究一种新的假说,即镍(II)引起DSB、DPC和
诱导遗传毒性拓扑异构酶I-DNA产物转化细胞。拟议的研究将
确定(1)Ni(II)诱导DSB同源重组修复缺陷的机理,(2)
易出错的DSB修复在镍(II)致癌基因改变产生中的重要性,以及
(3)镍诱导的含拓扑异构酶I的DPC和DPC的形成及其病理生理意义
DNA断裂。这项工作的完成有望揭示人类免疫缺陷的分子机制。
非致突变致癌物镍致癌基因异常的形成及新鉴定
这种金属造成DNA损伤的生物标志物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Anatoly Zhitkovich其他文献
Anatoly Zhitkovich的其他文献
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{{ truncateString('Anatoly Zhitkovich', 18)}}的其他基金
Indirect Genotoxicity in Metal Carcinogenesis
金属致癌过程中的间接遗传毒性
- 批准号:
10527323 - 财政年份:2020
- 资助金额:
$ 35.85万 - 项目类别:
Indirect Genotoxicity in Metal Carcinogenesis
金属致癌过程中的间接遗传毒性
- 批准号:
10304906 - 财政年份:2020
- 资助金额:
$ 35.85万 - 项目类别:
Regulation of p53 and Checkpoint Signaling by Chromium(VI)
Chromium(VI) 对 p53 和检查点信号传导的调节
- 批准号:
10306386 - 财政年份:2017
- 资助金额:
$ 35.85万 - 项目类别:
Regulation of p53 and Checkpoint Signaling by Chromium(VI)
Chromium(VI) 对 p53 和检查点信号传导的调节
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10057383 - 财政年份:2017
- 资助金额:
$ 35.85万 - 项目类别:
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