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Aryl hydrocarbon receptor (AHR) deficiency in a frog model of dioxin toxicity

二恶英毒性青蛙模型中芳基碳氢化合物受体（AHR）缺陷

基本信息

批准号：
10652101
负责人：
WADE H POWELL
金额：
$ 34.78万
依托单位：
KENYON COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652101
关键词：
Acute Adult Adverse effects African Agonist Amphibia Animals Apoptosis Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Biological Assay Biological Metamorphosis Cardiovascular system Cell Cycle Cell Cycle Regulation Cell Differentiation process Cell Line Cell physiology Cells Chemical Exposure Chemicals Cultured Cells Data Defect Deformity Development Dioxins Diploidy Disease Edema Embryo Embryonic Development Environment Environmental Pollutants Exhibits Fetal Development Flow Cytometry Frequencies Future Gene Expression Alteration Gene Proteins Gene Targeting Generations Genes Genomics Head Health Hepatic Histology Human Immune Individual Industrial Waste Knock-out Larva Length Life Ligands Measures Mediating Modeling Molecular Morphology Mus Mutation Null Lymphocytes Oocytes Organogenesis Ovarian Pathway interactions Persons Petroleum Phenotype Physicians Play Ploidies Process Proliferating Propidium Diiodide Protein Deficiency Proteins Rana Regimen Risk Assessment Role Sampling Scientist Severities Stains Standardization Tadpoles Testing Tetrachlorodibenzodioxin Thyroid Gland Tissues Toxic effect Toxicology Training Variant Weather Western Blotting Work Xenopus Xenopus laevis cigarette smoke comparative developmental disease developmental toxicity embryo/fetus gastrulation genome editing human disease improved insight liver development mature animal mutant paralogous gene pollutant protein function protein structure receptor teratogenesis thyroid disruption transcription factor transcriptome sequencing undergraduate student

项目摘要

Project Summary. The Aryl Hydrocarbon Receptor protein (AHR) underlies multiple human disease states. AHR is a ligand-activated transcription factor that mediates toxicity of numerous environmental contaminants, including dioxin-like compounds such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) from industrial waste and polynuclear aromatic hydrocarbons in weathered crude oil and cigarette smoke. AHR also plays roles in ordinary development of liver, cardiovascular system, and oocytes, disruption of which by toxic agonists or mutation can cause disease in adults. African clawed frogs, pseudotetraploid Xenopus laevis and diploid X. tropicalis, are widely studied aquatic models of vertebrate development. Xenopus is also used in developmental toxicity screens at two life stages. FETAX (Frog Embryo Teratogenesis Assay-Xenopus) detects acute developmental toxicity resulting from chemical exposure at early life stages. The Amphibian Metamorphosis Assay (AMA) models late fetal development in humans, measuring chemical disruption of remodeling of a tadpole to a froglet. The human-health relevance of AHR function in developmental toxicity is poorly understood in frogs, limiting the validity of these assays for human risk assessment. An understanding of the fundamental developmental and cellular functions of frog AHRs is essential for the use of this model in toxicological studies. The overall objective is to use genome-edited, AHR-deficient Xenopus models, including ahr-null X. tropicalis animals and X. laevis cell lines, to identify specific functions of AHRs in developing frogs and cultured cells. Studies under Aim 1 will identify functions of AHR in X. tropicalis development. We will characterize phenotypes displayed in ahr-null frogs, using the FETAX regimen to compare frequency and severity of typical developmental defects in ahr-null and wild-type embryos, including survival, length, axial and head deformities, and edemas. We will also test the hypothesis that ahr-null frogs display hepatic and ovarian phenotypes typical of AHR-/- mice, comparing morphology and histology. Finally, we will use a suite of assays to determine how loss of ahr alters tissue remodeling during metamorphosis. We will couple morphological endpoints with RNAseq studies to determine gene expression alterations underlying phentoypes. In Aim 2, we will use X. laevis cell lines lacking one of the two ahr paralogs in this species, testing the hypothesis that individual AHR paralogs play distinct role in cell cycle regulation. We will compare slow-growing ahr1a-null mutants with ahr1b-null and wild-type XLK-WG cells by flow-cytometry, establishing cell cycle distribution of each. We will also test the hypothesis that ahr1a-null cells are prone to apoptosis. Preliminary data suggest that AHR1a and AHR1b regulate distinct sets of gene targets. We will test this hypothesis in RNAseq studies. This AREA project will provide comparative insight into the pathways of AHR-mediated developmental toxicity shared among vertebrate models. It will also lend mechanistic underpinning to frog developmental toxicity screens such as FETAX and AMA, improving their validity for human risk assessment.

项目总结。芳烃受体蛋白（AHR）是多种人类疾病状态的基础。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ARNT gene multiplicity in amphibians: characterization of ARNT2 from the frog Xenopus laevis.

DOI：
10.1002/jez.b.45
发表时间：
2003-12
期刊：
Journal of experimental zoology. Part B, Molecular and developmental evolution
影响因子：
0
作者：
A. J. Rowatt;John J. DePowell;W. Powell
通讯作者：
A. J. Rowatt;John J. DePowell;W. Powell

Developmental differences in elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during Xenopus laevis development.

非洲爪蟾发育过程中消除 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 的发育差异。