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      Large-Scale Assessment of the Zebrafish Embryo as a Possible Predictive Model in Toxicity Testing

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      1 , 1 , 2 , 1 , *

      PLoS ONE

      Public Library of Science

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          Abstract

          Background

          In the drug discovery pipeline, safety pharmacology is a major issue. The zebrafish has been proposed as a model that can bridge the gap in this field between cell assays (which are cost-effective, but low in data content) and rodent assays (which are high in data content, but less cost-efficient). However, zebrafish assays are only likely to be useful if they can be shown to have high predictive power. We examined this issue by assaying 60 water-soluble compounds representing a range of chemical classes and toxicological mechanisms.

          Methodology/Principal Findings

          Over 20,000 wild-type zebrafish embryos (including controls) were cultured individually in defined buffer in 96-well plates. Embryos were exposed for a 96 hour period starting at 24 hours post fertilization. A logarithmic concentration series was used for range-finding, followed by a narrower geometric series for LC 50 determination. Zebrafish embryo LC 50 (log mmol/L), and published data on rodent LD 50 (log mmol/kg), were found to be strongly correlated (using Kendall's rank correlation tau and Pearson's product-moment correlation). The slope of the regression line for the full set of compounds was 0.73403. However, we found that the slope was strongly influenced by compound class. Thus, while most compounds had a similar toxicity level in both species, some compounds were markedly more toxic in zebrafish than in rodents, or vice versa.

          Conclusions

          For the substances examined here, in aggregate, the zebrafish embryo model has good predictivity for toxicity in rodents. However, the correlation between zebrafish and rodent toxicity varies considerably between individual compounds and compound class. We discuss the strengths and limitations of the zebrafish model in light of these findings.

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          Most cited references 47

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          Zebrafish comparative genomics and the origins of vertebrate chromosomes.

          To help understand mechanisms of vertebrate genome evolution, we have compared zebrafish and tetrapod gene maps. It has been suggested that translocations are fixed more frequently than inversions in mammals. Gene maps showed that blocks of conserved syntenies between zebrafish and humans were large, but gene orders were frequently inverted and transposed. This shows that intrachromosomal rearrangements have been fixed more frequently than translocations. Duplicated chromosome segments suggest that a genome duplication occurred in ray-fin phylogeny, and comparative studies suggest that this event happened deep in the ancestry of teleost fish. Consideration of duplicate chromosome segments shows that at least 20% of duplicated gene pairs may be retained from this event. Despite genome duplication, zebrafish and humans have about the same number of chromosomes, and zebrafish chromosomes are mosaically orthologous to several human chromosomes. Is this because of an excess of chromosome fissions in the human lineage or an excess of chromosome fusions in the zebrafish lineage? Comparative analysis suggests that an excess of chromosome fissions in the tetrapod lineage may account for chromosome numbers and provides histories for several human chromosomes.
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            Headwaters of the zebrafish -- emergence of a new model vertebrate.

            The understanding of vertebrate development has advanced considerably in recent years, primarily due to the study of a few model organisms. The zebrafish, the newest of these models, has risen to prominence because both genetic and experimental embryological methods can be easily applied to this animal. The combination of approaches has proven powerful, yielding insights into the formation and function of individual tissues, organ systems and neural networks, and into human disease mechanisms. Here, we provide a personal perspective on the history of zebrafish research, from the assembly of the first genetic and embryological tools through to sequencing of the genome.
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              In vivo imaging of transport and biocompatibility of single silver nanoparticles in early development of zebrafish embryos.

              Real-time study of the transport and biocompatibility of nanomaterials in early embryonic development at single-nanoparticle resolution can offer new knowledge about the delivery and effects of nanomaterials in vivo and provide new insights into molecular transport mechanisms in developing embryos. In this study, we directly characterized the transport of single silver nanoparticles into an in vivo model system (zebrafish embryos) and investigated their effects on early embryonic development at single-nanoparticle resolution in real time. We designed highly purified and stable (not aggregated and no photodecomposition) nanoparticles and developed single-nanoparticle optics and in vivo assays to enable the study. We found that single Ag nanoparticles (5-46 nm) are transported into and out of embryos through chorion pore canals (CPCs) and exhibit Brownian diffusion (not active transport), with the diffusion coefficient inside the chorionic space (3 x 10(-9) cm(2)/s) approximately 26 times lower than that in egg water (7.7 x 10(-8) cm(2)/s). In contrast, nanoparticles were trapped inside CPCs and the inner mass of the embryos, showing restricted diffusion. Individual Ag nanoparticles were observed inside embryos at each developmental stage and in normally developed, deformed, and dead zebrafish, showing that the biocompatibility and toxicity of Ag nanoparticles and types of abnormalities observed in zebrafish are highly dependent on the dose of Ag nanoparticles, with a critical concentration of 0.19 nM. Rates of passive diffusion and accumulation of nanoparticles in embryos are likely responsible for the dose-dependent abnormalities. Unlike other chemicals, single nanoparticles can be directly imaged inside developing embryos at nanometer spatial resolution, offering new opportunities to unravel the related pathways that lead to the abnormalities.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                28 June 2011
                : 6
                : 6
                Affiliations
                [1 ]Institute of Biology, Sylvius Laboratory, Leiden University, Leiden, The Netherlands
                [2 ]Mathematical Institute, Leiden University, Leiden, The Netherlands
                University of Birmingham, United Kingdom
                Author notes

                Conceived and designed the experiments: SA MKR HGJvM. Performed the experiments: SA. Analyzed the data: SA MKR HGJvM. Contributed reagents/materials/analysis tools: MKR. Wrote the paper: SA MKR.

                Article
                PONE-D-11-05407
                10.1371/journal.pone.0021076
                3125172
                21738604
                Ali et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 11
                Categories
                Research Article
                Biology
                Developmental Biology
                Embryology
                Model Organisms
                Animal Models
                Zebrafish
                Toxicology
                Predictive Toxicology
                Toxic Agents
                Zoology
                Animal Physiology

                Uncategorized

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