Comparative analysis of goitrogenic effects of phenylthiourea and methimazole in zebrafish embryos

Fetter, Éva; Baldauf, Lisa; Fonte, Dillon F. Da; Ortmann, Julia; Scholz, Stefan

doi:10.1016/j.reprotox.2015.04.012

Cited by 30 publications

(24 citation statements)

References 59 publications

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“…Given the negative feedback mechanism that regulates TH synthesis, hyper- and hypothyroidism may be efficiently detected and measured by differences of intensity in the tg:mCherry fluorescence. The fluorescence signal is correlated with the expression of genes involved in the TH synthesis [ 22 ]. The transgenic strain allows detection of thyroid disruption without any sample preparation by observation of fluorescence using a microscope.…”

Section: Introductionmentioning

confidence: 99%

An automated screening method for detecting compounds with goitrogenic activity using transgenic zebrafish embryos

et al. 2018

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The knowledge on environmentally relevant chemicals that may interfere with thyroid signaling is scarce. Here, we present a method for the screening of goitrogens, compounds that disrupt the thyroid gland function, based on the automatic orientation of zebrafish in a glass capillary and a subsequent imaging of reporter gene fluorescence in the thyroid gland of embryos of the transgenic zebrafish line tg(tg:mCherry). The tg(tg:mCherry) reporter gene indicates a compensatory upregulation of thyroglobulin, the thyroid hormone precursor, in response to inhibition of thyroid hormone synthesis. Fish embryos were exposed to a negative control compound (3,4-dichloroaniline), or a concentration series of known goitrogenic compounds (resorcinol, methimazole, potassium perchlorate, 6-propyl-2-thiouracil, ethylenethiourea, phloroglucinol, pyrazole) with maximum exposure concentration selected based on mortality and/or solubility. Exposure to 3,4-dichloroaniline decreased the fluorescence signal. All goitrogenic compounds exhibited clear concentration-dependent inductions of reporter fluorescence 1.4 to 2.6 fold above control levels. Concentration-response modelling was used to calculate goitrogenic potencies based on EC50 values. The new automated method offers an efficient screening approach for goitrogenic activity.

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Section: Introductionmentioning

confidence: 99%

An automated screening method for detecting compounds with goitrogenic activity using transgenic zebrafish embryos

et al. 2018

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“…Molecular endpoints derived from toxicogenomic responses provided other endpoints that allow us to demonstrate the presence of compounds with a specific, potentially tissue-specific mode of action 3 4 5 6 . This observation has led to the development of transgenic biosensor lines that utilize genetic regulatory elements to drive the expression of fluorescent proteins and thereby report the presence of target classes of substances in the environment, such as estrogenic compounds 7 8 9 10 , dioxins 11 , heavy metals 12 13 14 , goitrogens 15 and glucocorticoids 16 17 18 . Interestingly, many of these biosensor genes exhibit tissues preferably responsive to particular classes of pollutants 6 .…”

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Zebrafish biosensor for toxicant induced muscle hyperactivity

Shahid

Takamiya

Stegmaier

et al. 2016

Sci Rep

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Robust and sensitive detection systems are a crucial asset for risk management of chemicals, which are produced in increasing number and diversity. To establish an in vivo biosensor system with quantitative readout for potential toxicant effects on motor function, we generated a transgenic zebrafish line TgBAC(hspb11:GFP) which expresses a GFP reporter under the control of regulatory elements of the small heat shock protein hspb11. Spatiotemporal hspb11 transgene expression in the musculature and the notochord matched closely that of endogenous hspb11 expression. Exposure to substances that interfere with motor function induced a dose-dependent increase of GFP intensity beginning at sub-micromolar concentrations, while washout of the chemicals reduced the level of hspb11 transgene expression. Simultaneously, these toxicants induced muscle hyperactivity with increased calcium spike height and frequency. The hspb11 transgene up-regulation induced by either chemicals or heat shock was eliminated after co-application of the anaesthetic MS-222. TgBAC(hspb11:GFP) zebrafish embryos provide a quantitative measure of muscle hyperactivity and represent a robust whole organism system for detecting chemicals that affect motor function.

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“…Given that the fish ELS test includes the embryonic period, exposure could be restricted to the embryonic period, if endpoints related to relevant modes of action and predictive of chronic toxicity could be identified and already measured in embryonic stages. For some of the major modes of action leading to enhanced ACRs or toxic ratios described in the present study, appropriate fish embryo assays have been developed and described: 1) the alterations in embryonic behavior (movements) have been shown to identify neurotoxicity (Klüver et al ); 2) endocrine‐disrupting effects can already be detected in fish embryos using, for example, aromatase as a sensitive target gene in a transgenic zebrafish model (Brion et al )—likewise, thyroid hormone–disrupting compounds (Fetter et al ; Thienpont et al ) and androgens (Sébillot et al ) can be identified using fish embryos; and 3) the lysyl oxidase–inhibiting dithiocarbamates provoked visible notochord distortion (Tilton et al ; van Boxtel et al ), indicating that the observation of malformations may serve as an indicator of potential enhanced fish ELS toxicity.…”

Section: Discussionmentioning

confidence: 99%

Meta‐analysis of fish early life stage tests—Association of toxic ratios and acute‐to‐chronic ratios with modes of action

Scholz

Schreiber

Armitage

et al. 2018

Enviro Toxic and Chemistry

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Fish early life stage (ELS) tests (Organisation for Economic Co-operation and Development test guideline 210) are widely conducted to estimate chronic fish toxicity. In these tests, fish are exposed from the embryonic to the juvenile life stages. To analyze whether certain modes of action are related to high toxic ratios (i.e., ratios between baseline toxicity and experimental effect) and/or acute-to-chronic ratios (ACRs) in the fish ELS test, effect concentrations (ECs) for 183 compounds were extracted from the US Environmental Protection Agency's ecotoxicity database. Analysis of ECs of narcotic compounds indicated that baseline toxicity could be observed in the fish ELS test at similar concentrations as in the acute fish toxicity test. All nonnarcotic modes of action were associated with higher toxic ratios, with median values ranging from 4 to 9.3 Â 10 4 (uncoupling < reactivity < neuromuscular toxicity < methemoglobin formation < endocrine disruption < extracellular matrix formation inhibition). Four modes of action were also found to be associated with high ACRs: 1) lysyl oxidase inhibition leading to notochord distortion, 2) putative methemoglobin formation or hemolytic anemia, 3) endocrine disruption, and 4) compounds with neuromuscular toxicity. For the prediction of ECs in the fish ELS test with alternative test systems, endpoints targeted to the modes of action of compounds with enhanced toxic ratios or ACRs could be used to trigger fish ELS tests or even replace these tests. Environ Toxicol Chem 2018;37:955-969. C 2018 SETAC

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Comparative analysis of goitrogenic effects of phenylthiourea and methimazole in zebrafish embryos

Cited by 30 publications

References 59 publications

An automated screening method for detecting compounds with goitrogenic activity using transgenic zebrafish embryos

An automated screening method for detecting compounds with goitrogenic activity using transgenic zebrafish embryos

Zebrafish biosensor for toxicant induced muscle hyperactivity

Meta‐analysis of fish early life stage tests—Association of toxic ratios and acute‐to‐chronic ratios with modes of action

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