Exploring arsenic and its metabolites in a transgenic model

在转基因模型中探索砷及其代谢物

• 批准号: 7842476
• 负责人: IAIN L CARTWRIGHT
• 金额: $ 22.11万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842476
• 关键词: Accounting; Acute; Address; Affect; Ally; Anabolism; Animal Model; Appearance; Area; Arsenic; Arsenicals; Arsenites; Bangladesh; Biological; Biological Assay; Cancer Etiology; Carbon; Carcinogens; Cell Cycle; Cells; Chromosome abnormality; Chronic; Communities; Complex; Cultured Cells; DNA; Development; Disasters; Disease model; Dissection; Drosophila genus; Drug Metabolic Detoxication; Environmental Health; Enzymes; Evaluation; Excretory function; Exposure to; Force of Gravity; Future; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Health; Homologous Gene; Human; Human Pathology; Individual; Ingestion; Intake; Investigation; Lead; Learning; Light; Long-Term Effects; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Methionine; Methylation; Methyltransferase; Modeling; Molecular; Monitor; Nature; Organ; Organism; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Pathology; Pathway interactions; Pattern; Poison; Population; Predisposition; Process; Production; Public Health; Relative (related person); Resources; Role; Screening procedure; Severities; Signaling Pathway Gene; Skin; System; Techniques; Testing; Time; Tissues; Toxic effect; Toxicogenetics; Transgenes; Transgenic Animals; Transgenic Model; Transgenic Organisms; Transplantation; Urine; Variant; Water Pollution; Water Supply; drinking water; fly; genetic resource; global environment; in vivo; in vivo Model; insight; interest; mutant; overexpression; oxidative damage; public health relevance; research study; response; toxic metal; tumor; tumorigenesis; tumorigenic; uptake

DESCRIPTION (provided by applicant): Among the most serious issues confronting the global public health community is the long term consequence of arsenic ingestion in drinking water, a situation that has affected an estimated 100 million people worldwide, albeit disproportionately so in Bangladesh and West Bengal owing to the widespread provision of wells drawing arsenic-laced groundwater. Though arsenic is a well-known acute poison of oxidative phosphorylation when ingested in large quantities, chronic, low-level exposure leads to a variety of pathologies, among which are numerous forms of cancer. Mechanistically it has proven difficult to assign the specific cause of arsenic-induced cancer, though DNA and/or chromosomal aberrations typically accompany its appearance, and there has been much debate regarding whether or not arsenic can act as a complete carcinogen. Moreover, progress in these areas has been hampered by a relative lack of suitable animal models. Recently, the realization that metabolic methylation of arsenic may actually lead to a more potent carcinogen rather than to its presumed detoxification has prompted interest in the mechanism of methylation, the species formed, and the possibility that polymorphisms in the gene(s) involved in uptake, metabolism and excretion of arsenic may have profound effects on susceptibility of exposed individuals. To address some of these issues with a well-defined, genetically amenable, in vivo system we propose to create a Drosophila transgenic model, in which control, and precise analysis, of arsenic methylation (catalyzed by human gene variants that occur naturally in the population) can be married with a variety of in vivo assays investigating specific features of DNA metabolism (oxidative damage, strand breakage, recombination), cellular response (chromosomal aberrations, cell cycle aberrations), and carcinogenic potential via tumor formation in a transplantation assay. With the enormous versatility available in the Drosophila system, allowing controllable over- and underexpression of virtually any endogenous gene to be easily achieved, it is anticipated that critical molecular pathways intersected by arsenic and its methylated metabolites can be identified as a result of phenotypic variation occurring in one or more of the above assays when tested in such altered genetic backgrounds. Thus, we propose that a model higher eukaryotic organism, one that has consistently proved to be an unparalleled resource in uncovering critical molecular features of numerous human pathological conditions, can be harnessed to shed light on a vitally important toxicogenetic problem. PUBLIC HEALTH RELEVANCE: The long-term ingestion of arsenic via drinking water by human populations in many parts of the world has proven to be one of the largest global public health disasters of modern times owing to the variety of detrimental health consequences that ensue, including numerous forms of organ cancer. Though much of interest has been learned from studies in cultured cells, investigation of the mechanisms by which this toxic metal affects biological pathways (particularly in its ability to cause cancer) has been hampered by a relative lack of good animal models that duplicate the human pathologies. We aim to develop a model for arsenic cellular toxicity and tumorigenesis by introducing critical human genes involved in arsenic metabolism into the fruit fly, Drosophila, where a combination of assays, allied to the unparalleled genetic manipulability of this organism, are anticipated to shed new light on questions related to how arsenic induces cancer and why individuals show widely variable susceptibility to its effects.

描述（由申请人提供）：全球公共卫生社区面临的最严重的问题是饮用水中砷摄入的长期后果，这种情况影响了全世界估计有1亿人，尽管在孟加拉国和西孟加拉邦都不成比例，这是由于井井有条而广泛的绘制了植物性的植物植物范围。尽管砷是一种众所周知的急性急性毒性毒性毒性，当大量摄入，但慢性，低水平的暴露会导致多种病理，其中是多种形式的癌症。从机械上讲，事实证明，很难分配砷诱导的癌症的特定原因，尽管DNA和/或染色体畸变通常伴随着其外观，并且关于砷是否可以充当完整的致癌物，存在很多争论。此外，相对缺乏合适的动物模型，这些领域的进展受到了阻碍。最近，认识到，砷的代谢甲基化实际上可能导致更有效的致癌物，而不是推测的解毒，这引起了人们对甲基化的机制，形成的物种的兴趣，以及在基因中的多态性涉及摄取，代谢性和排泄物的可能性可能呈现出对抗抗菌的效果的可能性。为了通过一个明确的，遗传上的，可融合的体内系统来解决其中一些问题，我们建议创建一个果蝇转基因模型，在该模型中，对砷甲基化的控制和精确的分析，砷甲基化（由人类自然在人群中自然发生的人类基因变异催化）可以与各种体内的特定特定特定特定特征（DNA METIBLISP）结婚（人口中）细胞反应（染色体畸变，细胞周期像差）和通过移植测定中肿瘤形成的致癌潜力。伴随果蝇系统中可用的巨大多功能性，可以轻松实现任何内源性基因的可控过度和不充分的压力，因此可以预见，可以在一种或更肯定的是在上面的疾病中鉴定出一种遗传的疾病，因此可以将砷及其甲基化代谢产物相交的关键分子途径可以鉴定出来。因此，我们提出，一种模型较高的真核生物，该模型始终被证明是一种无与伦比的资源，可以利用众多人类病理状况的临界分子特征，可以利用以阐明一个至关重要的毒理问题。公共卫生相关性：事实证明，由于随之而来的多种有害健康后果，包括多种形式的器官癌，人们事实证明，世界许多地区人口中的人口长期摄入砷是现代全球最大的公共卫生灾害之一。尽管从培养细胞的研究中学到了很多兴趣，但对这种有毒金属影响生物学途径（尤其是引起癌症的能力）的机制的研究受到了相对缺乏复制人类病理学的良好动物模型的阻碍。我们旨在通过将砷代谢中涉及的关键人类基因引入果蝇果蝇（Drosophila）中，与无与伦比的遗传操纵性相关的果蝇的结合，预计与对个人有关的新事物与癌症的影响相关，并将其与癌症相关的新事物，并将其与癌症相关的新光线，从而开发了砷细胞毒性和肿瘤发生的模型，该果蝇的结合与无与伦比的遗传操纵性相关。