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Zebrafish 2.0: A Model for Toxicological Research

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (1 April 2019) | Viewed by 66012

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Prof. Dr. Juliette Legler

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Institute for Risk Assessment Sciences, Department of Population Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
Interests: endocrine disrupting chemicals; obesity; adipogenesis; test development and validation
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Dear Colleagues,

The zebrafish (Danio rerio) has long been used as a model species for the toxicity testing of chemicals. The zebrafish, however, offers considerably more as a model species and is now used in many different research fields including basic developmental biology, neurobiology, and immunology. Advances in genetic and epigenetic research of the zebrafish, including gene knockout and transgenesis technologies, allow for better understanding of molecular mechanisms of toxic action. The potential of zebrafish for modeling human diseases is becoming increasingly evident, and the availability of these models allows for increased understanding of the role of chemical exposure in human disease. In this Special Issue, we welcome contributions that show recent developments in zebrafish toxicity testing and drug discovery, such as novel endpoints, assays and testing strategies. Articles covering aspects of molecular and cellular mechanisms of action to effects on individual fish as well as multigenerational effects and population level impacts are invited. Contributions on high throughput screening, monitoring and safety assessment of chemicals are invited, as well as new insights on the effects in chemical exposure in zebrafish models of human diseases. Translational studies that employ molecular methods to enhance our understanding of human health or environmental risk assessment are also of interest.

Prof. Dr. Juliette Legler
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

toxicology
ecotoxicology
pharmacology
toxicity testing
developmental biology
human health
disease genetics
epigenetics
zebrafish
vertebrate
hazard assessment
risk assessment
molecular mechanisms
high throughput screening
multigenerational
systems biology
translational study

Related Special Issue

Zebrafish: A Model for Toxicological Research in International Journal of Molecular Sciences (39 articles)

Published Papers (10 papers)

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Research

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20 pages, 2929 KiB

Open AccessArticle

Multiplex Analysis Platform for Endocrine Disruption Prediction Using Zebrafish

by Sergio Jarque, Jone Ibarra, Maria Rubio-Brotons, Jessica García-Fernández and Javier Terriente

Int. J. Mol. Sci. 2019, 20(7), 1739; https://doi.org/10.3390/ijms20071739 - 08 Apr 2019

Cited by 22 | Viewed by 4440

Abstract

Small fish are an excellent experimental model to screen endocrine-disrupting compounds, but current fish-based assays to detect endocrine disruption have not been standardized yet, meaning that there is not consensus on endpoints and biomarkers to be measured. Moreover, exposure conditions may vary depending on the species used as the experimental model and the endocrine pathway evaluated. At present, a battery of a wide range of assays is usually needed for the complete assessment of endocrine activities. With the aim of providing a simple, robust, and fast assay to assess endocrine-disrupting potencies for the three major endocrine axes, i.e., estrogens, androgens, and thyroid, we propose the use of a panel of eight gene expression biomarkers in zebrafish larvae. This includes brain aromatase (cyp19a1b) and vitellogenin 1 (vtg1) for estrogens, cytosolic sulfotransferase 2 family 2 (sult2st3) and cytochrome P450 2k22 (cyp2k22) for androgens, and thyroid peroxidase (tpo), transthyretin (ttr), thyroid receptor α (trα), and iodothyronine deiodinase 2 (dio2) for thyroid metabolism. All of them were selected according to their responses after exposure to the natural ligands 17β-estradiol, testosterone, and 3,3′,5-triiodo-L-thyronine (T3), respectively, and subsequently validated using compounds reported as endocrine disruptors in previous studies. Cross-talk effects were also evaluated for all compounds. Full article

(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)

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14 pages, 1696 KiB

Open AccessArticle

Safety Assessment of Compounds after In Vitro Metabolic Conversion Using Zebrafish Eleuthero Embryos

by Arianna Giusti, Xuan-Bac Nguyen, Stanislav Kislyuk, Mélanie Mignot, Cecilia Ranieri, Johan Nicolaï, Marlies Oorts, Xiao Wu, Pieter Annaert, Noémie De Croze, Marc Léonard, Annelii Ny, Deirdre Cabooter and Peter de Witte

Int. J. Mol. Sci. 2019, 20(7), 1712; https://doi.org/10.3390/ijms20071712 - 06 Apr 2019

Cited by 9 | Viewed by 4460

Abstract

Zebrafish-based platforms have recently emerged as a useful tool for toxicity testing as they combine the advantages of in vitro and in vivo methodologies. Nevertheless, the capacity to metabolically convert xenobiotics by zebrafish eleuthero embryos is supposedly low. To circumvent this concern, a comprehensive methodology was developed wherein test compounds (i.e., parathion, malathion and chloramphenicol) were first exposed in vitro to rat liver microsomes (RLM) for 1 h at 37 °C. After adding methanol, the mixture was ultrasonicated, placed for 2 h at −20 °C, centrifuged and the supernatant evaporated. The pellet was resuspended in water for the quantification of the metabolic conversion and the detection of the presence of metabolites using ultra high performance liquid chromatography-Ultraviolet-Mass (UHPLC-UV-MS). Next, three days post fertilization (dpf) zebrafish eleuthero embryos were exposed to the metabolic mix diluted in Danieau’s medium for 48 h at 28 °C, followed by a stereomicroscopic examination of the adverse effects induced, if any. The novelty of our method relies in the possibility to quantify the rate of the in vitro metabolism of the parent compound and to co-incubate three dpf larvae and the diluted metabolic mix for 48 h without inducing major toxic effects. The results for parathion show an improved predictivity of the toxic potential of the compound. Full article

(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)

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17 pages, 2668 KiB

Open AccessArticle

Thyroid Hormone Disruptors Interfere with Molecular Pathways of Eye Development and Function in Zebrafish

by Lisa Baumann, Helmut Segner, Albert Ros, Dries Knapen and Lucia Vergauwen

Int. J. Mol. Sci. 2019, 20(7), 1543; https://doi.org/10.3390/ijms20071543 - 27 Mar 2019

Cited by 29 | Viewed by 4708

Abstract

The effects of thyroid hormone disrupting chemicals (THDCs) on eye development of zebrafish were investigated. We expected THDC exposure to cause transcriptional changes of vision-related genes, which find their phenotypic anchoring in eye malformations and dysfunction, as observed in our previous studies. Zebrafish were exposed from 0 to 5 days post fertilization (dpf) to either propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, or tetrabromobisphenol-A (TBBPA), which interacts with thyroid hormone receptors. Full genome microarray analyses of RNA isolated from eye tissue revealed that the number of affected transcripts was substantially higher in PTU- than in TBBPA-treated larvae. However, multiple components of phototransduction (e.g., phosphodiesterase, opsins) were responsive to both THDC exposures. Yet, the response pattern for the gene ontology (GO)-class “sensory perception” differed between treatments, with over 90% down-regulation in PTU-exposed fish, compared to over 80% up-regulation in TBBPA-exposed fish. Additionally, the reversibility of effects after recovery in clean water for three days was investigated. Transcriptional patterns in the eyes were still altered and partly overlapped between 5 and 8 dpf, showing that no full recovery occurred within the time period investigated. However, pathways involved in repair mechanisms were significantly upregulated, which indicates activation of regeneration processes. Full article

(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)

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18 pages, 3090 KiB

Open AccessArticle

Comparison the Effect of Ferutinin and 17β-Estradiol on Bone Mineralization of Developing Zebrafish (Danio rerio) Larvae

by Hoda Zare Mirakabad, Mohammad Farsi, Saeed Malekzadeh Shafaroudi, Abdolreza Bagheri, Mehrdad Iranshahi and Nasrin Moshtaghi

Int. J. Mol. Sci. 2019, 20(6), 1507; https://doi.org/10.3390/ijms20061507 - 26 Mar 2019

Cited by 6 | Viewed by 4833

Abstract

There is an urgent need to develop novel drugs for osteoporosis which occurs due to estrogen deficiency. Phytoestrogens derived from medicinal plants would be the best alternative to chemical drugs with harmful side effects. The main purpose of the present study was to investigate the effect of ferutinin compared to 17β-estradiol (E2) on bone mineralization of zebrafish larvae. Regarding the lack of publications, the histology analysis was performed after exposure to E2 to find effective treatment on bone mineralization of developing zebrafish larvae. Then, the larvae were exposed to four concentrations of ferutinin at three time points to assess the mortality, the expression of some related genes and histology of the ceratohyal and hyomandibular of treated larvae. The RT-PCR result of the treatment groups demonstrated the similar expression pattern in the larvae which were exposed to 1.25 μg/mL of ferutinin and 2 µM of E2 at 2 dpf, which confirmed the result of histology analysis. In addition, RT-qPCR of high concentration of ferutinin and E2 demonstrated that bmp2a/b and esr1 were downregulated and upregulated when the larvae were exposed to 5 μg/mL of ferutinin and 10 µM of E2, respectively. Full article

(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)

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21 pages, 2243 KiB

Open AccessArticle

Optimizing the Use of Zebrafish Feeding Trials for the Safety Evaluation of Genetically Modified Crops

by Isabelle J. Gabriëls, Lucia Vergauwen, Marthe De Boevre, Stefan Van Dongen, Ronny Blust, Sarah De Saeger, Mia Eeckhout, Marc De Loose and Dries Knapen

Int. J. Mol. Sci. 2019, 20(6), 1472; https://doi.org/10.3390/ijms20061472 - 23 Mar 2019

Cited by 3 | Viewed by 3371

Abstract

In Europe, the toxicological safety of genetically modified (GM) crops is routinely evaluated using rodent feeding trials, originally designed for testing oral toxicity of chemical compounds. We aimed to develop and optimize methods for advancing the use of zebrafish feeding trials for the safety evaluation of GM crops, using maize as a case study. In a first step, we evaluated the effect of different maize substitution levels. Our results demonstrate the need for preliminary testing to assess potential feed component-related effects on the overall nutritional balance. Next, since a potential effect of a GM crop should ideally be interpreted relative to the natural response variation (i.e., the range of biological values that is considered normal for a particular endpoint) in order to assess the toxicological relevance, we established natural response variation datasets for various zebrafish endpoints. We applied equivalence testing to calculate threshold equivalence limits (ELs) based on the natural response variation as a method for quantifying the range within which a GM crop and its control are considered equivalent. Finally, our results illustrate that the use of commercial control diets (CCDs) and null segregant (NS) controls (helpful for assessing potential effects of the transformation process) would be valuable additions to GM safety assessment strategies. Full article

(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)

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9 pages, 963 KiB

Open AccessArticle

An Integrative Evaluation Method for the Biological Safety of Down and Feather Materials

by Toshikatsu Kawada, Junya Kuroyanagi, Fumiyoshi Okazaki, Mizuki Taniguchi, Hiroko Nakayama, Narumi Suda, Souta Abiko, Satoshi Kaneco, Norihiro Nishimura and Yasuhito Shimada

Int. J. Mol. Sci. 2019, 20(6), 1434; https://doi.org/10.3390/ijms20061434 - 21 Mar 2019

Cited by 5 | Viewed by 3605

Abstract

Background: Down and feather materials have been commonly used and promoted as natural stuffing for warm clothing and bedding. These materials tend to become more allergenic as they become contaminated with microorganisms, in addition to being subjected to several kinds of chemical treatments. The biological or chemical contaminants in these materials pose a major risk to human health, to consumers and manufacturers alike. Here, we report the development of an integrative evaluation method for down and feather materials to assess bacterial contamination and in vivo toxicity. Methods: To assess bacterial contamination, we quantified 16S ribosomal RNA, performed culture tests, and established a conversion formula. To determine in vivo toxicity, we performed a zebrafish embryo toxicity testing (ZFET). Results: Washing the material appropriately decreases the actual number of bacteria in the down and feather samples; in addition, after washing, 16S rRNA sequencing revealed that the bacterial compositions were similar to those in rinse water. The ZFET results showed that even materials with low bacterial contamination showed high toxicity or high teratogenicity, probably because of the presence of unknown chemical additives. Conclusions: We established an integrative evaluation method for down and feather safety, based on bacterial contamination with in vivo toxicity testing. Full article

(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)

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16 pages, 2368 KiB

Open AccessArticle

A Smart Imaging Workflow for Organ-Specific Screening in a Cystic Kidney Zebrafish Disease Model

by Gunjan Pandey, Jens H. Westhoff, Franz Schaefer and Jochen Gehrig

Int. J. Mol. Sci. 2019, 20(6), 1290; https://doi.org/10.3390/ijms20061290 - 14 Mar 2019

Cited by 14 | Viewed by 5883

Abstract

The zebrafish is being increasingly used in biomedical research and drug discovery to conduct large-scale compound screening. However, there is a lack of accessible methodologies to enable automated imaging and scoring of tissue-specific phenotypes at enhanced resolution. Here, we present the development of an automated imaging pipeline to identify chemical modifiers of glomerular cyst formation in a zebrafish model for human cystic kidney disease. Morpholino-mediated knockdown of intraflagellar transport protein Ift172 in Tg(wt1b:EGFP) embryos was used to induce large glomerular cysts representing a robustly scorable phenotypic readout. Compound-treated embryos were consistently aligned within the cavities of agarose-filled microplates. By interfacing feature detection algorithms with automated microscopy, a smart imaging workflow for detection, centring and zooming in on regions of interests was established, which enabled the automated capturing of standardised higher resolution datasets of pronephric areas. High-content screening datasets were processed and analysed using custom-developed heuristic algorithms implemented in common open-source image analysis software. The workflow enables highly efficient profiling of entire compound libraries and scoring of kidney-specific morphological phenotypes in thousands of zebrafish embryos. The demonstrated toolset covers all the aspects of a complex whole organism screening assay and can be adapted to other organs, specimens or applications. Full article

(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)

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30 pages, 5551 KiB

Open AccessArticle

From mRNA Expression of Drug Disposition Genes to In Vivo Assessment of CYP-Mediated Biotransformation during Zebrafish Embryonic and Larval Development

by Evy Verbueken, Chloé Bars, Jonathan S. Ball, Jelena Periz-Stanacev, Waleed F. A. Marei, Anna Tochwin, Isabelle J. Gabriëls, Ellen D. G. Michiels, Evelyn Stinckens, Lucia Vergauwen, Dries Knapen, Chris J. Van Ginneken and Steven J. Van Cruchten

Int. J. Mol. Sci. 2018, 19(12), 3976; https://doi.org/10.3390/ijms19123976 - 10 Dec 2018

Cited by 21 | Viewed by 4150

Abstract

The zebrafish (Danio rerio) embryo is currently explored as an alternative for developmental toxicity testing. As maternal metabolism is lacking in this model, knowledge of the disposition of xenobiotics during zebrafish organogenesis is pivotal in order to correctly interpret the outcome of teratogenicity assays. Therefore, the aim of this study was to assess cytochrome P450 (CYP) activity in zebrafish embryos and larvae until 14 d post-fertilization (dpf) by using a non-specific CYP substrate, i.e., benzyloxy-methyl-resorufin (BOMR) and a CYP1-specific substrate, i.e., 7-ethoxyresorufin (ER). Moreover, the constitutive mRNA expression of CYP1A, CYP1B1, CYP1C1, CYP1C2, CYP2K6, CYP3A65, CYP3C1, phase II enzymes uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and sulfotransferase 1st1 (SULT1ST1), and an ATP-binding cassette (ABC) drug transporter, i.e., abcb4, was assessed during zebrafish development until 32 dpf by means of quantitative PCR (qPCR). The present study showed that trancripts and/or the activity of these proteins involved in disposition of xenobiotics are generally low to undetectable before 72 h post-fertilization (hpf), which has to be taken into account in teratogenicity testing. Full capacity appears to be reached by the end of organogenesis (i.e., 120 hpf), although CYP1—except CYP1A—and SULT1ST1 were shown to be already mature in early embryonic development. Full article

(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)

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Review

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20 pages, 1692 KiB

Open AccessReview

The Olfactory System of Zebrafish as a Model for the Study of Neurotoxicity and Injury: Implications for Neuroplasticity and Disease

by Erika Calvo-Ochoa and Christine A. Byrd-Jacobs

Int. J. Mol. Sci. 2019, 20(7), 1639; https://doi.org/10.3390/ijms20071639 - 02 Apr 2019

Cited by 43 | Viewed by 14474

Abstract

The olfactory system, composed of the olfactory organs and the olfactory bulb, allows organisms to interact with their environment and through the detection of odor signals. Olfaction mediates behaviors pivotal for survival, such as feeding, mating, social behavior, and danger assessment. The olfactory organs are directly exposed to the milieu, and thus are particularly vulnerable to damage by environmental pollutants and toxicants, such as heavy metals, pesticides, and surfactants, among others. Given the widespread occurrence of olfactory toxicants, there is a pressing need to understand the effects of these harmful compounds on olfactory function. Zebrafish (Danio rerio) is a valuable model for studying human physiology, disease, and toxicity. Additionally, the anatomical components of the zebrafish olfactory system are similar to those of other vertebrates, and they present a remarkable degree of regeneration and neuroplasticity, making it an ideal model for the study of regeneration, reorganization and repair mechanisms following olfactory toxicant exposure. In this review, we focus on (1) the anatomical, morphological, and functional organization of the olfactory system of zebrafish; (2) the adverse effects of olfactory toxicants and injury to the olfactory organ; and (3) remodeling and repair neuroplasticity mechanisms following injury and degeneration by olfactory toxicant exposure. Full article

(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)

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26 pages, 1102 KiB

Open AccessReview

Zebrafish Models of Neurodevelopmental Disorders: Limitations and Benefits of Current Tools and Techniques

by Raquel Vaz, Wolfgang Hofmeister and Anna Lindstrand

Int. J. Mol. Sci. 2019, 20(6), 1296; https://doi.org/10.3390/ijms20061296 - 14 Mar 2019

Cited by 61 | Viewed by 14957

Abstract

For the past few years there has been an exponential increase in the use of animal models to confirm the pathogenicity of candidate disease-causing genetic variants found in patients. One such animal model is the zebrafish. Despite being a non-mammalian animal, the zebrafish model has proven its potential in recapitulating the phenotypes of many different human genetic disorders. This review will focus on recent advances in the modeling of neurodevelopmental disorders in zebrafish, covering aspects from early brain development to techniques used for modulating gene expression, as well as how to best characterize the resulting phenotypes. We also review other existing models of neurodevelopmental disorders, and the current efforts in developing and testing compounds with potential therapeutic value. Full article

(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)

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