Dioxin sensitivity of an amphibian toxicity test model

两栖动物毒性试验模型的二恶英敏感性

• 批准号: 6357695
• 负责人: WADE H POWELL
• 金额: $ 12.83万
• 依托单位: KENYON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6357695
• 关键词: Xenopus oocyte; aromatic hydrocarbon receptor; biological signal transduction; dioxins; environmental contamination; environmental exposure; environmental toxicology; evaluation /testing; molecular cloning; receptor binding; receptor expression; receptor sensitivity

DESCRIPTION (provided by applicant): Non-mammalian vertebrates are frequently used as model systems to determine the toxic, teratogenic, and carcinogenic properties of environmental contaminants. However, potential differences in sensitivity or toxic mechanisms in phylogenetically distant animals can confound interpretations and cloud the relevance of such toxicological data to human health. A clear understanding of the similarities and differences in the molecular mechanisms underlying contaminant effects in different species can greatly contribute to the evaluation of their suitability as toxicological models. FETAX (Frog Embryo Teratogenesis Assay - Xenopus), a widely employed, standardized toxicity test, uses frog embryos to measure the developmental toxicity of chemicals, complex mixtures, and environmental samples. However, the ability of FETAX to assess toxicity of halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), is suspect. HAH sensitivity of Xenopus laevis, the FETAX model species, has not been systematically characterized, but studies in other frog species suggest that as a group, frogs are among the most resistant vertebrates to TCDD toxicity. Thus, the risk associated with HAH contaminants in environmental samples could be inaccurately estimated by FETAX criteria. The toxic effects of HAHs are mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. Inherent properties of the AHR signal transduction pathway, including AHR expression levels and the binding affinity of AHR for xenobiotic ligands, can underlie variations in the sensitivity of different animal groups to HAH toxicity and the potency with which these compounds elicit characteristic biochemical responses. The overall objective of this project is to determine the toxic potency and molecular mechanisms of TCDD toxicity during development of Xenopus laevis. Through in vivo exposure studies, molecular cloning of AHR sequences, and biochemical assays of heterologously expressed AHR proteins, the proposed project will test the central hypothesis that Xenopus, like other frogs, is relatively insensitive to TCDD toxicity, and that this insensitivity results from properties intrinsic to the AHR signal transduction pathway. These studies should contribute substantially to the mechanistic understanding of the developmental toxicity of HAHs and the suitability of FETAX for assessing the toxicity of HAH-containing environmental samples.

描述（由申请人提供）：非哺乳类脊椎动物通常 用作模型系统，以确定毒性、致畸性和致癌性 环境污染物的特性。然而，潜在的差异 遗传学上远缘动物的敏感性或毒性机制， 混淆解释和云的相关性，这些毒理学数据， 人体健康清楚地认识到， 不同物种中污染物影响的分子机制可以 大大有助于评价其作为毒理学的适用性 模型FETAX（蛙胚胎致畸试验-非洲爪蟾），一种广泛使用的， 标准化的毒性测试，使用青蛙胚胎来测量发育 化学品、复杂混合物和环境样品的毒性。然而，在这方面， FETAX评价卤代芳烃毒性能力 2，3，7，8-四氯二苯并-对-二恶英（TCDD）是可疑的。哈 非洲爪蟾的敏感性，FETAX模式物种，还没有被 系统的特点，但研究其他青蛙物种表明， 青蛙是脊椎动物中对四氯二苯并对二恶英毒性抵抗力最强的一类。因此，在本发明中， 与环境样品中的HAH污染物相关的风险可能是 根据FETAX标准估计不准确。多环芳烃的毒性作用是 由芳烃受体（AHR）介导，配体激活 转录因子AHR信号转导的固有特性 途径，包括AHR表达水平和AHR对 异生物质配体，可以在不同的敏感性变化的基础上， 动物组的HAH毒性和这些化合物引起的效力 典型的生化反应该项目的总体目标是 确定TCDD毒性的毒性效力和分子机制， 非洲爪蟾的发育通过体内暴露研究， AHR序列的克隆和异源表达的AHR的生物化学测定， AHR蛋白，拟议的项目将测试的中心假设， 非洲爪蟾和其他青蛙一样，对TCDD毒性相对不敏感， 这种不灵敏性是由AHR信号固有的特性造成的 转导途径这些研究将大大有助于 对多环芳烃发育毒性的机理理解以及 FETAX用于评估含HAH环境毒性的适用性 样品