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）：非哺乳动物脊椎动物经常用作模型系统来确定有毒、致畸和致癌物质 环境污染物的特性。然而，潜在的差异 系统发育较远的动物的敏感性或毒性机制可以 混淆了解释并模糊了此类毒理学数据与 人类健康。对相同点和不同点有清晰的认识 不同物种污染物影响的分子机制可以 极大地有助于评估其作为毒理学的适用性 模型。 FETAX（青蛙胚胎致畸试验 - 非洲爪蟾），一种广泛使用的、 标准化毒性测试，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， FETAX 评估卤代芳烃毒性的能力 (HAH)，例如 2,3,7,8 四氯二苯并-对二恶英 (TCDD)，值得怀疑。哈尔滨 非洲爪蟾 (FETAX 模型物种) 的敏感性尚未得到证实 系统地表征，但对其他青蛙物种的研究表明， 青蛙是对 TCDD 毒性抵抗力最强的脊椎动物之一。因此， 与环境样品中 HAH 污染物相关的风险可能是 FETAX 标准估计不准确。 HAH 的毒性作用是 由配体激活的芳基烃受体 (AHR) 介导 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 的结合亲和力 异生配体，可能导致不同的敏感性发生变化 动物群体对 HAH 的毒性以及这些化合物引起的效力 特征性生化反应。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，分子 AHR 序列的克隆以及异源表达的生化测定 AHR 蛋白质，拟议的项目将测试中心假设： 非洲爪蟾与其他青蛙一样，对 TCDD 毒性相对不敏感，并且 这种不敏感性是由 AHR 信号固有的特性造成的 转导途径。这些研究应该对 对HAHs发育毒性的机制理解 FETAX 评估含 HAH 环境毒性的适用性 样品。