Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
人肺上皮细胞和成纤维细胞中的颗粒 Cr(VI) 毒理学
基本信息
- 批准号:10359325
- 负责人:
- 金额:$ 10.51万
- 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:2021-07-01 至 2021-10-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAnimalsAnti-Inflammatory AgentsAntiinflammatory EffectAntioxidantsAutomobile DrivingBRCA2 geneBeetsBetaineBiological MarkersBreast Cancer CellCancer EtiologyCarcinogensCell DeathCellsCessation of lifeChromium CompoundsChromosomal InstabilityDNADNA Double Strand BreakDataDouble Strand Break RepairEndothelial CellsEnvironmentEpithelial CellsEventExposure toFibroblastsFilamentFoodFundingGoalsHazardous SubstancesHealth BenefitHeritabilityHumanInflammasomeInflammationInflammatoryInflammatory ResponseInvestmentsLungLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMetalsMolecularMusNational Institute of Environmental Health SciencesNatural ProductsNeoplastic Cell TransformationNucleoproteinsOutcomeParticulatePathway interactionsPropertyProteinsPublic HealthRAD51C geneRattusRegulatory PathwayReportingResearchRiskRisk AssessmentRisk ManagementRoleSignal TransductionStructure of parenchyma of lungTestingToxicologyTranslatingUmbilical veinUnited StatesWorkWorkplaceXRCC2 geneanti-cancerarmcancer cellcarcinogenesiscarcinogenicitychromium hexavalent iongenotoxicityhomologous recombinationimprovedin vivoinsightneoplasticneoplastic cellnovel strategiesparent grantpotential biomarkerpreventresponsetargeted biomarkertherapeutic targettumortumor progression
项目摘要
PROJECT SUMMARY OF THE FUNDED PARENT GRANT
Lung cancer continues to be the leading cause of cancer death in the U.S. One of the key strategies to combating
it is to better understand its causes. Hexavalent chromium [Cr(VI)] is a human lung carcinogen of major public
health concern because exposure to it is common in the workplace and in the general environment. Our study
focuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis, which are currently unknown. In
particular, this work focuses on the particulate Cr(VI) compounds, because they are the most potent Cr(VI)
carcinogens. Recent studies indicate particulate Cr(VI) induces chromosome instability and causes cells to
evade DNA double strand break repair, which are hallmarks of human lung cancer. Thus, this research focuses
on how particulate Cr(VI) induces cells to evade DNA double strand break repair leading to chromosome
instability and carcinogenesis. Our data show prolonged exposure to particulate Cr(VI) specifically impacts the
effector arm of homologous recombination (HR repair), disrupting RAD51 nucleoprotein filament formation, loss
of which can cause chromosome instability. Therefore, the goal of this research is to characterize this impact on
HR repair and the underlying changes in order to understand the mechanisms involved. Our hypothesis is:
particulate Cr(VI) disrupts the underlying mechanisms of RAD51 nucleoprotein filament formation inactivating
HR repair of Cr(VI)-induced DNA breaks resulting in CIN and neoplastic transformation. We will test this
hypothesis through three interrelated specific aims. Aim 1 will determine how Cr(VI) impacts BRCA2, DSS1,
RAD51B, RAD51C, RAD51D, RPA, and XRCC2 to disrupt RAD51 nucleoprotein filament formation in human
lung cells. Aim 2 determines the persistence and cellular heritability of disrupted RAD51 filament formation in
human lung cells neoplastically transformed by Cr(VI), and the protein levels of BRCA2, DSS1, RAD51B,
RAD51C, RAD51D, RPA, and XRCC2 in lung tumors from human Cr(VI) workers. Aim 3 determines the impact
of Cr(VI) on protein levels of BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 in the lungs and
lung tumors of Cr(VI)-exposed animals. Results will lead to the first reports of detailed information of the
interactions of Cr(VI) with the effector arm of HR repair at a cellular and molecular level and the first
characterizations of these aspects in neoplastic outcomes including tumors from Cr(VI)-exposed workers.
Results will also show which changes are transient and depend on exposure and which changes persist in cells
that escape cell death and progress to neoplastic outcomes. This research is significant because it provides: 1)
An understanding of Cr(VI)’s carcinogenic mechanism; 2) Essential information to better assess exposure risk
to particulates; and 3) A mechanistic approach for further study of Cr(VI), other metals and lung cancer in general.
基金资助的奖学金项目摘要
肺癌仍然是美国癌症死亡的主要原因,这是对抗癌症的关键策略之一
是为了更好地了解其原因。六价铬[Cr(VI)]是一种主要的人类肺癌致癌物
由于在工作场所和一般环境中暴露于它是很常见的,因此对健康的关注。我们的研究
重点研究Cr(VI)诱导的致癌机制,这是目前未知的。在
特别是,这项工作的重点是颗粒状Cr(VI)化合物,因为它们是最有效的Cr(VI)
致癌物质。最近的研究表明,颗粒铬(VI)诱导染色体不稳定性,并导致细胞
逃避DNA双链断裂修复,这是人类肺癌的标志。因此,本研究重点
颗粒状Cr(VI)如何诱导细胞逃避DNA双链断裂修复,导致染色体
不稳定性和致癌作用。我们的数据显示,长期暴露于颗粒状Cr(VI)会特别影响
同源重组效应臂(HR修复),破坏RAD 51核蛋白丝形成,丢失
其中之一会导致染色体不稳定。因此,本研究的目标是描述这种影响,
HR修复和潜在的变化,以了解所涉及的机制。我们的假设是:
颗粒Cr(VI)破坏了RAD 51核蛋白丝形成失活的潜在机制
Cr(VI)诱导的DNA断裂的HR修复导致CIN和肿瘤转化。我们将测试这个
通过三个相互关联的具体目标的假设。目标1将确定Cr(VI)如何影响BRCA 2,DSS 1,
RAD 51 B、RAD 51 C、RAD 51 D、RPA和XRCC 2破坏人RAD 51核蛋白丝形成
肺细胞目的2确定在哺乳动物中破坏的RAD 51丝形成的持续性和细胞遗传性。
用Cr(VI)致瘤转化的人肺细胞,和BRCA 2,DSS 1,RAD 51 B,
来自人Cr(VI)工作者的肺肿瘤中的RAD 51 C、RAD 51 D、RPA和XRCC 2。目标3确定影响
Cr(VI)对肺中BRCA 2、DSS 1、RAD 51 B、RAD 51 C、RAD 51 D、RPA和XRCC 2蛋白水平的影响,
暴露于Cr(VI)的动物的肺肿瘤。结果将导致第一次报告的详细资料,
Cr(VI)与HR修复效应臂在细胞和分子水平上的相互作用,
这些方面的特点在肿瘤的结果,包括肿瘤铬(VI)暴露的工人。
结果还将显示哪些变化是短暂的,取决于暴露,哪些变化在细胞中持续存在
逃避细胞死亡并发展为肿瘤的结果。这项研究意义重大,因为它提供了:1)
了解Cr(VI)的致癌机制; 2)更好地评估暴露风险的基本信息
3)进一步研究铬(VI),其他金属和肺癌的一般机制的方法。
项目成果
期刊论文数量(47)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Chromium effects on glucose tolerance and insulin sensitivity in persons at risk for diabetes mellitus.
- DOI:10.4158/ep10131.or
- 发表时间:2011-01
- 期刊:
- 影响因子:0
- 作者:Ali A;Ma Y;Reynolds J;Wise JP Sr;Inzucchi SE;Katz DL
- 通讯作者:Katz DL
Hexavalent chromium is cytotoxic and genotoxic to American alligator cells.
- DOI:10.1016/j.aquatox.2015.12.004
- 发表时间:2016-02
- 期刊:
- 影响因子:0
- 作者:Wise SS;Wise C;Xie H;Guillette LJ Jr;Zhu C;Wise JP Jr;Wise JP Sr
- 通讯作者:Wise JP Sr
A review of the toxicity of chemical dispersants.
- DOI:10.1515/reveh.2011.035
- 发表时间:2011
- 期刊:
- 影响因子:3.9
- 作者:Wise J;Wise JP Sr
- 通讯作者:Wise JP Sr
Hexavalent Chromium-Induced Chromosome Instability Drives Permanent and Heritable Numerical and Structural Changes and a DNA Repair-Deficient Phenotype.
- DOI:10.1158/0008-5472.can-18-0531
- 发表时间:2018-08-01
- 期刊:
- 影响因子:11.2
- 作者:Wise SS;Aboueissa AE;Martino J;Wise JP Sr
- 通讯作者:Wise JP Sr
One Environmental Health: an emerging perspective in toxicology.
一个环境健康:毒理学的新兴观点。
- DOI:10.12688/f1000research.14233.1
- 发表时间:2018
- 期刊:
- 影响因子:0
- 作者:Pérez,Adam;PierceWiseSr,John
- 通讯作者:PierceWiseSr,John
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
John Pierce Wise其他文献
Global assessment of oceanic lead pollution using sperm whales (<em>Physeter macrocephalus</em>) as an indicator species
- DOI:
10.1016/j.marpolbul.2013.12.007 - 发表时间:
2014-02-15 - 期刊:
- 影响因子:
- 作者:
Laura C. Savery;Sandra S. Wise;Carolyne Falank;James Wise;Christy Gianios;W. Douglas Thompson;Christopher Perkins;Tongzhang Zheng;Cairong Zhu;John Pierce Wise - 通讯作者:
John Pierce Wise
Does aluminum exposure of pregnant animals lead to accumulation in mothers or their offspring?
怀孕动物接触铝是否会导致母亲或其后代体内积累铝?
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:0
- 作者:
J. Borak;John Pierce Wise - 通讯作者:
John Pierce Wise
Particulate hexavalent chromium inhibits global transcription of genes in DNA repair pathways, particularly targeting homologous recombination repair, base excision repair, mismatch repair and microhomology-mediated end-joining
颗粒状六价铬抑制 DNA 修复途径中基因的整体转录,尤其靶向同源重组修复、碱基切除修复、错配修复和微同源介导的末端连接。
- DOI:
10.1016/j.jhazmat.2024.136892 - 发表时间:
2025-03-05 - 期刊:
- 影响因子:11.300
- 作者:
Idoia Meaza;Caitlin R. Cahill;Rachel M. Speer;J. Calvin Kouokam;John Pierce Wise - 通讯作者:
John Pierce Wise
Global assessment of arsenic pollution using sperm whales (<em>Physeter macrocephalus</em>) as an emerging aquatic model organism
- DOI:
10.1016/j.cbpc.2014.01.003 - 发表时间:
2014-06-01 - 期刊:
- 影响因子:
- 作者:
Laura C. Savery;James T.F. Wise;Sandra S. Wise;Carolyne Falank;Christy Gianios;W. Douglas Thompson;Christopher Perkins;Tongzhang Zheng;Cairong Zhu;John Pierce Wise - 通讯作者:
John Pierce Wise
Carcinogenic Mechanisms of Hexavalent Chromium: From DNA Breaks to Chromosome Instability and Neoplastic Transformation
- DOI:
10.1007/s40572-024-00460-9 - 发表时间:
2024-10-28 - 期刊:
- 影响因子:9.100
- 作者:
Idoia Meaza;Aggie R. Williams;Sandra S. Wise;Haiyan Lu;John Pierce Wise - 通讯作者:
John Pierce Wise
John Pierce Wise的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('John Pierce Wise', 18)}}的其他基金
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10601677 - 财政年份:2022
- 资助金额:
$ 10.51万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10655683 - 财政年份:2022
- 资助金额:
$ 10.51万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10459886 - 财政年份:2022
- 资助金额:
$ 10.51万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10883861 - 财政年份:2022
- 资助金额:
$ 10.51万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10792258 - 财政年份:2021
- 资助金额:
$ 10.51万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10456862 - 财政年份:2021
- 资助金额:
$ 10.51万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10656428 - 财政年份:2021
- 资助金额:
$ 10.51万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10198235 - 财政年份:2021
- 资助金额:
$ 10.51万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 10.51万 - 项目类别:
Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
人肺上皮细胞和成纤维细胞中的颗粒 Cr(VI) 毒理学
- 批准号:
8074274 - 财政年份:2010
- 资助金额:
$ 10.51万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 10.51万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 10.51万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 10.51万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 10.51万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 10.51万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 10.51万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 10.51万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 10.51万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 10.51万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 10.51万 - 项目类别:
Grant-in-Aid for Early-Career Scientists