The zebrafish embryo as a model for assessing off-target drug effects

Strähle, Uwe; Grabher, Clemens

doi:10.1242/dmm.006312

Cited by 30 publications

(22 citation statements)

References 40 publications

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“…Because these screens have recently been thoroughly reviewed elsewhere (MacRae and Peterson, 2003;Peterson et al, 2004;Zon and Peterson, 2005;Wheeler and Brandli, 2009;Peal et al, 2010;Strahle and Grabher, 2010;Taylor et al, 2010), we will only highlight a few important examples here. In one striking early success, a small molecule screen identified two chemical suppressors of the zebrafish gridlock mutation (in the transcriptional repressor hey2 gene), which disrupts normal aorta development and leads to a lack of circulation to the trunk and tail (Peterson et al, 2004).…”

Section: Small Molecule Screening In Zebrafishmentioning

confidence: 99%

Behavioral screening for neuroactive drugs in zebrafish

Rihel

Schier

2012

Developmental Neurobiology

110

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The larval zebrafish has emerged asa vertebrate model system amenable to small molecule screens for probing diverse biological pathways. Two large-scale small molecule screens examined the effects of thousands of drugs on larval zebrafish sleep/wake and photomotor response behaviors. Both screens identified hundreds of molecules that altered zebrafish behavior in distinct ways. The behavioral profiles induced by these small molecules enabled the clustering of compounds according to shared phenotypes. This approach identified regulators of sleep/wake behavior and revealed the biological targets for poorly characterized compounds. Behavioral screening for neuroactive small molecules in zebrafish is an attractive complement to in vitro screening efforts, because the complex interactions in the vertebrate brain can only be revealed in vivo.

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Section: Small Molecule Screening In Zebrafishmentioning

confidence: 99%

Behavioral screening for neuroactive drugs in zebrafish

Rihel

Schier

2012

Developmental Neurobiology

110

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“…In the last few years, several investigators have pursued such modeling in the zebrafish. The toxicology of virtually every organ system from the thyroid to the brain has been investigated 18, 55, 56 . Cardiotoxicity and hepatotoxicity have been particularly well studied, with extensive conservation of mechanism and outcome having been demonstrated between zebrafish and humans 57, 58 .…”

Section: Organ Specific Toxicologymentioning

confidence: 99%

Changing the scale and efficiency of chemical warfare countermeasure discovery using the zebrafish

Peterson

MacRae

2013

Drug Discovery Today: Disease Models

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As the scope of potential chemical warfare agents grows rapidly and as the diversity of potential threat scenarios expands with non-state actors, so a need for innovative approaches to countermeasure development has emerged. In the last few years, the utility of the zebrafish as a model organism that is amenable to high-throughput screening has become apparent and this system has been applied to the unbiased discovery of chemical warfare countermeasures. This review summarizes the in vivo screening approach that has been pioneered in the countermeasure discovery arena, and highlights the successes to date as well as the potential challenges in moving the field forward. Importantly, the establishment of a zebrafish platform for countermeasure discovery would offer a rapid response system for the development of antidotes to the continuous stream of new potential chemical warfare agents.

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“…The zebrafish model can be used to rapidly evaluate pharmaceuticals, such as tamoxifen, to identify novel effects and better understand drug side effects and toxicity (Barros et al , 2008; Strahle and Grabher, 2010; MacRae and Peterson, 2015). This increasingly popular and rapid throughput model can link unique adverse phenotypes with molecular events to elucidate mechanisms of action for toxicants in vivo (Hill et al , 2005; Bugel et al , 2014; Truong et al , 2014).…”

Section: 0 Introductionmentioning

confidence: 99%

Phenotype anchoring in zebrafish reveals a potential role for matrix metalloproteinases (MMPs) in tamoxifen's effects on skin epithelium

Bugel

Wehmas

et al. 2016

Toxicology and Applied Pharmacology

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The zebrafish is a powerful alternative model used to link phenotypes with molecular effects to discover drug mode of action. Using a zebrafish embryo-larval toxicity bioassay, we evaluated the effects of tamoxifen - a widely used anti-estrogen chemotherapeutic. Zebrafish exposed to ≥10 µM tamoxifen exhibited a unique necrotic caudal fin phenotype that was rapidly induced regardless of developmental life-stage when treatment was applied. To define tamoxifen’s bioactivity resulting in this phenotype, targeted gene expression was used to evaluate 100 transcripts involved in tissue remodeling, calcium signaling, cell cycle and cell death, growth factors, angiogenesis and hypoxia. The most robustly misregulated transcripts in the tail were matrix metalloproteinases mmp9 and mmp13a, induced 127 and 1145 fold, respectively. Expression of c-fos, c-jun, and ap1s1 were also moderately elevated (3–7 fold), consistent with AP-1 activity - a transcription factor that regulates MMP expression. Immunohistochemistry confirmed high levels of induction for MMP13a in affected caudal fin skin epithelial tissue. The necrotic caudal fin phenotype was significantly attenuated or prevented by three functionally unique MMP inhibitors: EDTA (metal chelator), GM 6001 (broad MMP inhibitor), and SR 11302 (AP-1 transcription factor inhibitor), suggesting MMP-dependence. SR 11302 also inhibited induction of mmp9, mmp13a, and a putative MMP target, igfbp1a. Overall, our studies suggest that tamoxifen’s effect is the result of perturbation of the MMP system in skin leading to ectopic expression, cytotoxicity, and the necrotic caudal fin phenotype. These studies help advance our understanding of tamoxifen’s non-classical mode of action and implicates a possible role for MMPs in tissues such as skin.

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The zebrafish embryo as a model for assessing off-target drug effects

Cited by 30 publications

References 40 publications

Behavioral screening for neuroactive drugs in zebrafish

Behavioral screening for neuroactive drugs in zebrafish

Changing the scale and efficiency of chemical warfare countermeasure discovery using the zebrafish

Phenotype anchoring in zebrafish reveals a potential role for matrix metalloproteinases (MMPs) in tamoxifen's effects on skin epithelium

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