TOXICOLOGY OF ENVIRONMENTAL CHEMICALS

研究在竞争性计划项目赠款更新，“毒性 环境化学品”，旨在了解 某些环境化学品的毒性机制，包括 卤化碳，对人类健康构成危害。 的总主题 跨学科研究将集中在化学诱导毒性 涉及蛋白质、核酸和基因表达， （1）化学相互作用的机制，包括烷基化和 受体改变、氧化应激和氧化还原状态;（2） 这些药物对蛋白质结构和功能以及基因表达的影响 包括硫醇烷基化和/或氧化对蛋白质的影响 结构，动力学和折叠;（3）对免疫的影响机制 和过氧化物酶体系统;和（4）分析工具，包括质量 光谱法和核磁共振（NMR），与分析 化学试剂及其与大分子相互作用的性质。 研究目的是：（1）阐明细胞凋亡的机制和动力学。 蛋白质折叠和氧化和/或烷基化的影响， 环境化学品。作为一个模型，该途径将被绘制为 重组人巨噬细胞集落刺激因子β的折叠 包括动力学的形成和分解作用 中间体，途径上的能量障碍和结构变化 通过酰胺氘/氢分析， （2）了解所选环境化学品的毒性 其通过氧化应激和/或硫醇烷基化改变氧化还原应变 并改变硫氧还蛋白家族的结构和功能， 蛋白质-硫氧还蛋白、硫氧还蛋白还原酶和蛋白质二硫化物 异构酶;（3）利用NMR确定烷基化和 蛋白质巯基的氧化还原状态对蛋白质结构，动力学， 功能，并确定蛋白质折叠研究中的中间体;（4） 阐明过氧化物酶体增殖物作用的分子决定因素 假设是通过与特定的 细胞内受体蛋白，过氧化物酶体增殖物激活受体 PPARalpha这些研究将为更好地 了解环境化学物质在引起氧化应激中的作用 以及调节控制中配体诱导的构象变化 蛋白质结构和功能;（5）研究生物化学和 诱导T细胞活化改变的分子机制 通过芳香族卤代烃TCDD，并阐明 抗原呈递中T细胞活化和氧化还原状态改变 细胞重要的是许多化学物质产生 氧化应激通过细胞内受体（即，啊 受体，PPARalpha）或通过诱导酶， 氧化应激 五个高度跨学科的项目将加强这一努力， 来回答关于化学和生物特性的主要问题， 环境化学品，这些项目的结果将是 用于为风险预测提供机械基础， 可能与人类暴露于环境有关的疾病 化学品

Research in the competitive Program Project Grant Renewal, "Toxicity of Environmental Chemicals", is directed toward the understanding of mechanisms of toxicity of selected environmental chemicals, including some halocarbons, that pose human health hazards. The overall theme of the interdisciplinary research will focus on chemically induced toxicity involving proteins, nucleic acids, and gene expression and will be devoted to: (1) mechanisms of chemical interactions including alkylations and receptors alterations, oxidative stress and redox status; (2) effects of such agents on protein structure and function and gene expression including effects of thiol alkylation and/or oxidation on protein structure, dynamics, and folding; (3) mechanisms of effects on the immune and peroxisome systems; and (4) analytical tools, including mass spectrometry and nuclear magnetic resonance (NMR), with which to analyze chemical agents and the nature of their interactions with macromolecules. Research objectives are to: (1) Elucidate the mechanisms and kinetics of protein folding and the effects of oxidation and/or alkylation by environmental chemicals. As a model, the pathway will be mapped for the folding of human recombinant macrophage colony stimulating factor beta including the role of formation and decomposition of kinetic intermediates, the energy barriers on the pathway, and structural changes that occur upon refolding as analyzed by amide deuterium/hydrogen exchange; (2) Understand the toxicity of selected environmental chemicals that, by oxidative stress and/or alkylation of thiols, alter redox strains and alter the structure and functions of the thioredoxin family of proteins-thioredoxin, thioredoxin reductase, and protein disulfide isomerase; (3) Utilize NMR to determine the effects of alkylation and redox status of protein thiols on protein structure, dynamics, and function, and to identify intermediates in protein folding studies; (4) Elucidate the molecular determinants of peroxisome proliferator action that are hypothesized to be mediated via interaction with a specific intracellular receptor protein, peroxisome proliferator-activated receptor PPARalpha. These studies will provide additional basis to better understand the role of environmental chemicals in causing oxidative stress as well as ligand-induced conformational change in the regulatory control of protein structure and function; and (5) Investigate the biochemical and molecular mechanisms underlying alterations in T cell activation induced by the aromatic halocarbon TCDD and elucidate the relationship between altered T cell activation and altered redox status in antigen presenting cells. Of importance is the ability of many chemicals to generate oxidative stress either through intracellular receptors (i.e., Ah receptor, PPARalpha) or through induction of enzymes that enzymes oxidative stress. The five highly interdisciplinary projects will strengthen the effort to answer major questions about the chemical and biological properties of environmental chemicals, and the findings from these projects will be utilized to provide a mechanistic basis for prediction of risks and possible disease associated with human exposure to environmental chemicals.