Zebrafish: A Marvel of High-Throughput Biology for 21st Century Toxicology (original) (raw)
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Environmental Science and Pollution Research, 2008
Background, aim, and scope The use of fish embryos is not regulated by current legislations on animal welfare and is therefore considered as a refinement, if not replacement of animal experiments. Fish embryos represent an attractive model for environmental risk assessment of chemicals since they offer the possibility to perform small-scale, high-throughput analyses. Main features Beyond their application for determining the acute toxicity, fish embryos are also excellent models for studies aimed at the understanding of toxic mechanisms and the indication of possible adverse and long-term effects. Therefore, we have reviewed the scientific literature in order to indicate alternative applications of the fish embryo model with focus on embryos of the zebrafish. Results and discussions The analysis of the mode of action is important for the risk assessment of environmental chemicals and can assist in indicating adverse and long-term effects. Toxicogenomics present a promising approach to unravel the potential mechanisms. Therefore, we present examples of the use of zebrafish embryos to study the effect of chemicals on gene and protein patterns, and the potential implications of differential expression for toxicity. The possible application of other methods, such as kinase arrays or metabolomic profiling, is also highlighted. Furthermore, we show examples of toxicokinetic studies (bioconcentration, ABC transporters) and discuss limitations that might be caused by the potential barrier function of the chorion. Finally, we demonstrate that biomarkers of endocrine disruption, immune modulation, genotoxicity or chronic toxicity could be used as indicators or predictors of sub-acute and long-term effects. Conclusions The zebrafish embryo represents a model with an impressive range of possible applications in environmental sciences. Particularly, the adaptation of molecular, system-wide approaches from biomedical research is likely to extend its use in ecotoxicology. Recommendations and perspectives Challenges for future research are (1) the identification of further suitable molecular markers as indicators of the mode of action, (2) the establishment of strong links between (molecular) effects in short-term assays in embryos and long-term (toxic) effects on individuals, (3) the definition of limitations of the model and (4) the development of tests that can be used for regulatory purposes.
Transcriptional profiling reveals barcode-like toxicogenomic responses in the zebrafish embryo
Genome Biology, 2007
http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Zebrafish toxicogenomic responses
Microarray profiling of zebrafish embryos exposed to a range of environmental toxicants revealed distinct expression profiles for each of the toxicants tested.
Abstract Background: Early life stages are generally most sensitive to toxic effects. Our knowledge on the action of manmade chemicals on the developing vertebrate embryo is, however, rather limited. We addressed the toxicogenomic response of the zebrafish embryo in a systematic manner by asking whether distinct chemicals would induce specific transcriptional profiles.Zebrafish embryos as models for embryotoxic and teratological effects of chemicals
Reproductive Toxicology, 2009
The experimental virtues of the zebrafish embryo such as small size, development outside of the mother, cheap maintenance of the adult made the zebrafish an excellent model for phenotypic genetic and more recently also chemical screens. The availability of a genome sequence and several thousand mutants and transgenic lines together with gene arrays and a broad spectrum of techniques to manipulate gene functions add further to the experimental strength of this model. Pioneering studies suggest that chemicals can have in many cases very similar toxicological and teratological effects in zebrafish embryos and humans. In certain areas such as cardiotoxicity, the zebrafish appears to outplay the traditional rodent models of toxicity testing. Several pilot projects used zebrafish embryos to identify new chemical entities with specific biological functions. In combination with the establishment of transgenic sensor lines and the further development of existing and new automated imaging systems, the zebrafish embryos could therefore be used as cost-effective and ethically acceptable animal models for drug screening as well as toxicity testing.
Toxicological Sciences, 2010
Large-scale toxicogenomic screening approaches offer great promise for generating a bias-free system-wide view of toxicological effects and modes-of-action of chemicals and ecotoxicants. However, early applications of microarray technology have identified relatively small groups of responding genes with which to define new targets for analysis by conventional means. We have trialled a more intensive approach to the design and interpretation of array experiments incorporating a balanced interwoven ANOVA design with higher levels of biological replication, a more thorough analysis of errors and false discovery rates, and an analysis of response patterns using gene network models. Zebrafish embryos were exposed from 1.5 h post-fertilization for 72 h to ecotoxicants representing different classes-2,4-dichlorophenol, 3,4-dichloroaniline, pentachlorophenol, and cadmium chloride-at low concentrations producing a developmental disturbance to 10% of embryos and half of this dose. Extracted whole embryo RNA was then analyzed on microarrays. Analysis revealed responses of 3000-5000 genes, which is 10-1000 times greater than previously reported, with significance at lower levels of fold change. Some gene responses were common to multiple toxicants, and others were restricted to just one or two toxicants. The gene expression profiles for the different toxicants were distinctive, and analysis using network-based models provided a high level of detail of affected processes, some of which were novel. This approach provides a more highly refined view of toxic effects, from which meaningful patterns of response can be discerned and related to functional deficits and from which more reliable indicators of toxicological effect can be predicted.
Chemical genetic screening in the zebrafish embryo
Nature Protocols, 2009
Chemical genetic screening can be described as a discovery approach in which chemicals are assayed for their effects on a defined biological system. The zebrafish, Danio rerio, is a well-characterized and genetically tractable vertebrate model organism that produces large numbers of rapidly developing embryos that develop externally. These characteristics allow for flexible, rapid and scalable chemical screen design using the zebrafish. We describe a protocol for screening compounds from a chemical library for effects on early zebrafish development using an automated in situ based read-out. As screenings are carried out in the context of a complete, developing organism, this approach allows for a more comprehensive analysis of the range of a chemical's effects than that provided by, for example, a cell culture-based or in vitro biochemical assay. Using a 24-h chemical treatment, one can complete a round of screening in 6 d.
Developmental toxicity screening in zebrafish
Birth defects research. Part C, Embryo today : reviews, 2011
Given the ever-increasing toxic exposure ubiquitously present in our environment as well as emerging evidence that these exposures are hazardous to human health, the current rodent-based regulations are proving inadequate. In the process of overhauling risk assessment methodology, a nonrodent test organism, the zebrafish, is emerging as tractable for medium- and high-throughput assessments, which may help to accelerate the restructuring of standards. Zebrafish have high developmental similarity to mammals in most aspects of embryo development, including early embryonic processes, and on cardiovascular, somite, muscular, skeletal, and neuronal systems. Here, we briefly describe the development of these systems and then chronicle the toxic impacts assessed following chemical exposure. We also compare the available data in zebrafish toxicity assays with two databases containing mammalian toxicity data. Finally, we identify gaps in our collective knowledge that are ripe for future studies. Birth Defects Research (Part C) 93:67–114, 2011. © 2011 Wiley-Liss, Inc.
Microchemical Journal, 2019
The Water Framework Directive (WFD) addresses the European Union Member States to achieve a good status of all water bodies. The WFD measures have allowed to reduce and eliminate the discharges, releases, and emissions of several priority substances with the aim of limiting the risks for the ecosystems and public health. Additionally, a Watch List (WL) for the monitoring of emerging contaminants was adopted to assess the environmental risk of new chemicals potentially toxic for water bodies. However, the amount of toxicants widespread in the environment is incredibly high and only a tiny fraction of substances is regularly monitored as established by the European legislation. Furthermore, the WFD does not involve a monitoring plan for chemical mixtures. Chemical analysis of water samples is essential for the monitoring programmes. However, it does not give full answers about the adverse effects of contaminants present in water bodies. In this context, the effect-based methods (i.e. bioassays and biomarkers) are essential tools to implement the monitoring strategies and reach the ambitious goals included in the WFD. Zebrafish early stages, i.e. embryos and early larvae, represent a very successful vertebrate model to assess the toxic effects on aquatic organisms and to subsequently perform a valid ecosystem monitoring. Indeed, this animal model raises many advantages and allows the definition of many toxicant modes of action (MoA). In this review, we report a large number of literature studies that performed experimental analysis using zebrafish embryos and early larvae to investigate the effects of the compounds included into the WFD and the related WL. We show how the zebrafish embryo model is able to detect and identify different toxicity mechanisms and specific effects with a great level of accuracy. Our goal is to promote the use of this effect-based method in the water monitoring strategies and to improve its use for regulatory purposes.
Zebrafish as Toxicological model for screening and recapitulate human diseases
Journal of unexplored medical data, 2018
Embryonic and larval Danio rerio (zebrafish) is increasingly used as a toxicological model to conduct rapid in vivo tests and developmental toxicity assays; the zebrafish features high genetic homology to mammals, robust, phenotypes, highthroughput genetic and chemical screening have made it a powerful tool to evaluate in vivo toxicity. New methodologies of genome editing as CRISPR/Cas9; ZFN and TALEN make it a suitable model to perform studies to pair human genetic diseases as well. This review surveys recent studies employing zebrafish as experimental model, comparing it with other in vivo and in vitro models, presenting zebrafish as a potent vertebrate tool to evaluate drug toxicity and efficacy in order to facilitate more extensive, easy and comprehensive knowledge of new generation drugs.