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April 01, 2009 (Vol. 29, No. 7)

High-Content Methods to Assess Toxicity

Extensions to Thermo Scientific Cellomics Platform Address Comet and Zebrafish Applications

  • Zebrafish

    Click Image To Enlarge +
    Figure 2. Embryos were treated two days post-fertilization (2 dpf) with three different compounds to elicit morphological change due to toxicity.

    Over the past few years, zebrafish embryos have become an increasingly important tool for biologists as a model to study development. The zebrafish has become important because the embryo is highly transparent (easing analysis), genes are highly conserved (around 75%) with humans, it is a vertebrate, and the embryo develops quickly.

    Large numbers of offspring make them amenable for large-scale small molecule or genetic screens. In addition hundreds of transgenic zebrafish lines exist, many with GFP tags that allow for detailed investigations into gene function. It is not surprising therefore that zebrafish are also seen as a suitable system for studying toxicity in an animal model that is cheaper, more scalable, and more humane than rodents for example. The fact that the developing embryo is highly sensitive to a toxic insult makes the zebrafish system a highly relevant in vivo model for use by drug discovery, environmental, and even consumer products toxicity testing.

    Analysis of hundreds of embryos for the subtle morphological and other changes in response to a toxic insult represents a challenge. With the recent release of the ZebraTox BioApplication for the Cellomics Arrayscan HCS platform, however, researchers can now bring the power of high content to the assessment of toxicity in zebrafish.

    The Zebrafish BioApplication allows analysis of either Brightfield (transmitted light, nonfluorescently labeled) embryos or those that are fluorescently labeled. The application measures a sophisticated range of morphological changes in response to a toxic insult, such as shape, curvature, and area.

    Zebrafish tend to curl up in response to a toxicant (Figure 2), and this can be measured and a dose range defined. Figure 3  shows the results of an in-house study looking at four different compounds; the graph clearly quantifies the degree of toxicity based on the morphological measurements. The BioApplication coupled with the Arrayscan platform and utilizing 96- or 384-well plates can screen large numbers of compounds in minutes, yielding highly relevant data. In addition, using fluorescently labeled zebrafish the application can evaluate for angiogenesis, neuronal development and so on, allowing deeper insights into mechanisms of toxicity.

    There is no doubt that there is pressure on many fronts to change the way toxicity testing is done—from the viewpoint of improving predictivity, through scaling relevant manual assays, to more relevant models of human toxicity. With recent extensions to Thermo Scientific high-content platform (Comet and Zebra fish toxicity assessment), coupled with the long standing multiparameter cytotoxicty evaluation, we have a real chance to improve human health in terms of safer drugs (for lowered costs), understanding the effect of environmental toxins, and as ensuring that the products we use, from shampoos to topical skin treatments, are safe.

  • Click Image To Enlarge +
    Figure 3. Graph shows the percent change for three of the reported features of the ZebraTox BioApplication as compared to vehicle control of 1.0% DMSO.

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