HEALTH EFFECTS OF TOXIC SUBSTANCES
有毒物质对健康的影响
基本信息
- 批准号:7358992
- 负责人:
- 金额:$ 1.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-09-01 至 2007-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The significance of chemicals in the environment is a critical National Health concern. A focus of the Toxic Substances Program at UC-Berkeley is to understand the health risks posed by hazardous waste sites, which requires the ability to understand how chemicals from those sites are absorbed , distributed, metabolized and excreted (ADME) from animals and humans. Our studies aim to measure ADME of human exposure to benzene. Benzene in the environment can be toxic a such low concentrations that ADME is difficult to measure with conventional methods such as LC-MS. Our goal is to circumvent this problem by developing a method to covalently attach a 14C-labeled species to benzene-modified biological molecules such as DNA. This ¿postlabeling¿ will allow measurement of DNA damaged caused by benzene metabolites in humans by AMS without exposure to high concentrations of toxicants. We developed such an assay using a model compound known as 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP), a rodent carcinogen whose metabolites can bind to DNA. This model was chosen due to its well-known ADME and low volatility in order to prevent contamination of the laboratory by radiocarbon labeled benzene. Proof-of-principle studies were carried out using an enzyme called polynucleotidyl terminal transferase (TnT) and a 14C-labled 2¿,3¿-dideoxythymidine triphosphate (ddTTP). The enzyme catalyzed the transfer of radiolabeled thymidine to PhIP adducted oligonucleotides. SIGNIFICANCE This method can be extended to benzene-DNA adducts if the appropriate enzymes digest conditions are developed.
该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者(PI)可能从另一个NIH来源获得主要资金,因此可以在其他CRISP条目中表示。所列机构为中心,不一定是研究者所在机构。化学品在环境中的重要性是一个关键的国家健康问题。加州大学伯克利分校有毒物质计划的重点是了解危险废物场地带来的健康风险,这需要了解这些场地的化学品如何从动物和人类吸收,分布,代谢和排泄(ADME)。 我们的研究旨在测量人体暴露于苯的ADME。苯在环境中可以是有毒的,这样的低浓度,ADME是难以测量与传统的方法,如LC-MS。我们的目标是规避这个问题,通过开发一种方法,共价连接14 C-标记的物种苯修饰的生物分子,如DNA。这……后标记将允许在不暴露于高浓度毒物的情况下,通过AMS测量人体中苯代谢物引起的DNA损伤。 我们开发了这样一种测定方法,使用一种称为2-氨基-1-甲基-6-苯基咪唑[4,5 b]吡啶(PhIP)的模型化合物,这是一种啮齿动物致癌物,其代谢物可以与DNA结合。选择该模型是因为其众所周知的ADME和低挥发性,以防止放射性碳标记的苯污染实验室。使用一种名为多核苷酸末端转移酶(TnT)的酶和14 C标记的2 ',3'-二脱氧胸苷三磷酸(ddTTP)进行了原理验证研究。该酶催化放射性标记的胸苷转移到PhIP加合的寡核苷酸。 如果开发出合适的酶消化条件,该方法可扩展至苯-DNA加合物。
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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