Dioxin sensitivity of an amphibian toxicity test model

描述(申请人提供)：非哺乳类脊椎动物经常被用作模型系统来确定有毒、致畸和致癌 环境污染物的性质。然而，潜在的差异在于 在系统发育上遥远的动物中的敏感性或毒性机制 令人困惑的解释，并使此类毒物学数据与 人类健康。认清中英关系的异同 不同物种中污染物影响的分子机制可能 极大地有助于评估它们作为毒物学的适宜性 模特们。FETAX(青蛙胚胎致畸试验)是一种应用广泛的， 标准化毒性试验，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评价卤代芳烃毒性的能力 (HAHS)，如2，3，7，8四氯二苯并对二恶英(TCDD)是可疑的。哈哈 非洲爪哇，FETAX模式物种，其敏感度还没有 有系统的特征，但对其他青蛙物种的研究表明 青蛙是对TCDD毒性最具抵抗力的脊椎动物之一。因此， 与环境样本中的六六六污染物相关的风险可能是 FETAX标准估计不准确。HAHS的毒性作用是 由配体激活的芳香烃受体(AHR)介导 转录因子。AHR信号转导的固有特性 途径，包括AHR的表达水平和与AHR的结合亲和力 异源生物配体，可以导致不同敏感度的不同 对动物群体的毒性和这些化合物诱导的效力 典型的生化反应。这个项目的总体目标是 确定TCDD毒性的效力和分子机制 非洲爪哇的开发利用通过体内暴露研究，分子 AHR序列的克隆及异源表达产物的生化检测 AHR蛋白质，拟议的项目将检验以下中心假设 非洲爪蛙和其他青蛙一样，对TCDD的毒性相对不敏感， 这种不敏感性是由于AHR信号固有的特性造成的 转导途径。这些研究应该会对 从机理上理解HAHS的发育毒性 FETAX在评价含HAH环境毒性中的适用性 样本。

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.