Molecular Effects of Low Level Arsen

低浓度砷的分子效应

• 批准号: 6901463
• 负责人: A J GANDOLFI
• 金额: $ 17.07万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901463
• 关键词: arsenic; chemical kinetics; environmental exposure; environmental toxicology; free radical oxygen; glutathione; hazardous substances; kidney; membrane permeability; metal metabolism; oxidative stress; tissue /cell culture; toxin metabolism; ubiquitin; urinary bladder; water pollution

Low-level exposure (1-50 ppb) arsenic causes a multitude of toxic effects. The new drinking water standard for arsenic (10 ppb) is based on the occurrence of bladder cancer. The mechanism(s) by which arsenic produces bladder cancer are unknown. Additionally the toxic effects of low-level arsenic exposure to produce bladder injury have not been adequately examined. Our studies will examine mechanisms of low-level arsenic exposure to bladder tissue. An immortalized human epithelial cell line (UTOtsa) will be the primary model system. In preliminary studies UROtsa cells were shown to be capable of biotransforming inorganic arsenic to more toxic methylated metabolites and low-level (1-50 ppb) arsenic chemical species were cytotoxic to the cells. Our Aims are to: 1.) Determine the role of biotransformation of arsenic in bladder to produce sub-cytotoxic effects. The biotransformation of inorganic arsenic will be manipulated to determine which arsenic metabolite is the ultimate toxicant. 2.) Determine if the low-level arsenic exposure to the bladder is producing toxicity via proteotoxic mechanisms. This study will examine if arsenic species produce toxic effects via direct interaction with critical sulfhydryl targets. 3.) Determine if the low-level arsenic exposure to the bladder produces toxicity via an oxidative stress mechanism. The production of reactive oxygen species and the ensuing toxic effects will be profiled for various arsenic chemical species, 4.) Determine if the low-level arsenic exposure to the bladder is affecting the ubiquitin pathway and its toxic consequences. Arsenic has been shown to alter the processing of proteins in a cell. Our studies show low-level arsenic to cause and an accumulation of ubiquinated proteins. Our studies will characterize this accumulation, identify if specific proteins are accumulated, and determine the impact of these accumulated proteins on cell viability. 5.) Determine if biomarkers of arsenic toxicity to the bladder result from the preceding studies. Bladder samples from surgical patients will be used for in vitro toxicity studies with arsenic to determine if we see similar effects to those seen with the cells and if the potential biomarkers are present (ubiquinated proteins). Overall, these studies will clarify the toxic effects of low-level arsenic in a human bladder model and provide potential biomarkers for arsenic-induced bladder injury.

低剂量暴露（1-50 ppb）砷会引起多种毒性作用。新的饮用水砷标准（10 ppb）是基于膀胱癌的发生。砷导致膀胱癌的机制尚不清楚。此外，低水平砷暴露对膀胱损伤的毒性作用尚未得到充分研究。我们的研究将检验低水平砷暴露于膀胱组织的机制。永生化人上皮细胞系（UTOtsa）将作为主要的模型系统。初步研究表明，UROtsa细胞能够将无机砷生物转化为毒性更强的甲基化代谢物和低水平（1-50 ppb）砷化学物质