Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury

Morello, Judit; Derks, Rico; Lopes, Susana S.; Steenvoorden, Evelyne; Monteiro, Emília C.; Mayboroda, Oleg A.; Pereira, Sofia A.

doi:10.3389/fphar.2018.01193

Cited by 13 publications

(7 citation statements)

References 42 publications

(51 reference statements)

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“…Three drugs known to cause tubulopathy in humans (paracetamol, gentamicin, and tenofovir) were shown to induce functional, morphological, and histopathological kidney changes in zebrafish larvae . Metabolic changes in biomarkers (purines, glutathione, and amino acids) associated with acute kidney injury were detected in larval zebrafish exposed to those same three drugs . Beyond proof-of-concept for detecting nephrotoxicity, the larval zebrafish are being used in phenotypic screens to discover compounds with a potential to repair acute kidney injury …”

Section: Nephrotoxicitymentioning

confidence: 99%

Use of Zebrafish in Drug Discovery Toxicology

Cassar

Adatto

Freeman

et al. 2019

Chem. Res. Toxicol.

384

277

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Unpredicted human safety events in clinical trials for new drugs are costly in terms of human health and money. The drug discovery industry attempts to minimize those events with diligent preclinical safety testing. Current standard practices are good at preventing toxic compounds from being tested in the clinic; however, false negative preclinical toxicity results are still a reality. Continual improvement must be pursued in the preclinical realm. Higher-quality therapies can be brought forward with more information about potential toxicities and associated mechanisms. The zebrafish model is a bridge between in vitro assays and mammalian in vivo studies. This model is powerful in its breadth of application and tractability for research. In the past two decades, our understanding of disease biology and drug toxicity has grown significantly owing to thousands of studies on this tiny vertebrate. This Review summarizes challenges and strengths of the model, discusses the 3Rs value that it can deliver, highlights translatable and untranslatable biology, and brings together reports from recent studies with zebrafish focusing on new drug discovery toxicology. ■ CONTENTS 107Biographies 107 References 108

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Section: Nephrotoxicitymentioning

confidence: 99%

Use of Zebrafish in Drug Discovery Toxicology

Cassar

Adatto

Freeman

et al. 2019

Chem. Res. Toxicol.

384

277

View full text Add to dashboard Cite

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“…Complementing the aforementioned efforts, multiple studies have focused on defining the zebrafish metabolome in both its wild-type state 12,13 and in the contexts of development 14–16 , regeneration 17 , and toxin response 18–20 . Ong et al .…”

Section: Introductionmentioning

confidence: 99%

Parallel Reaction Monitoring reveals structure-specific ceramide alterations in the zebrafish

Zhang

Trauger

Vidoudez

et al. 2019

Sci Rep

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Extensive characterisations of the zebrafish genome and proteome have established a foundation for the use of the zebrafish as a model organism; however, characterisation of the zebrafish lipidome has not been as comprehensive. In an effort to expand current knowledge of the zebrafish sphingolipidome, a Parallel Reaction Monitoring (PRM)-based liquid chromatography-mass spectrometry (LC-MS) method was developed to comprehensively quantify zebrafish ceramides. Comparison between zebrafish and a human cell line demonstrated remarkable overlap in ceramide composition, but also revealed a surprising lack of most sphingadiene-containing ceramides in the zebrafish. PRM analysis of zebrafish embryogenesis identified developmental stage-specific ceramide changes based on long chain base (LCB) length. A CRISPR-Cas9-generated zebrafish model of Farber disease exhibited reduced size, early mortality, and severe ceramide accumulation where the amplitude of ceramide change depended on both acyl chain and LCB lengths. Our method adds an additional level of detail to current understanding of the zebrafish lipidome, and could aid in the elucidation of structure-function associations in the context of lipid-related diseases.

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“…Glutathione exhibits significant antioxidant activity in organisms. Due to its significant role in the deactivation of reactive oxygen species, it is usually synthesized in ubiquitous amounts to cope with oxidative stress [ 32 ]. In our case, glutathione metabolism was stimulated only in the zebrafish exposed to non-doped CNDs.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling Unveils the Impact of Non-Doped and Heteroatom-Doped Carbon Nanodots on Zebrafish (Danio rerio) Embryos

et al. 2021

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Recently, concern has been raised over the transport, transformation, and fate of carbon nanodots (CNDs) after their release into the environment. Their toxicity towards organisms and humans has recently been addressed as an important issue. In this study, a metabolomic approach was employed to obtain an insight into the effect of CNDs (either pristine or doped with nitrogen and nitrogen/sulfur) on zebrafish. Embryos were exposed to concentrations corresponding to lethal concentration (LC) LC50 (550, 400, and 150 μg mL−1), LC50/2 (275, 200, and 75 μg mL−1), and LC50/4 (138, 100, and 38 μg mL−1) of the three CNDs (non-doped, N-doped, and N,S-codoped, respectively) to scrutinize the interactions of the CNDs with the larvae. Numerous differences in the metabolic pathways were recorded in all cases. Seven metabolic pathways were detected in the control larvae. When the larvae were exposed to concentrations equal to LC50, LC50/2, and LC50/4 of non-doped CNDs, 12, 12, and 3 metabolic pathways were detected, respectively. In the case of N-doped CNDs, 4, 7, and 4 pathways were detected, while in the case of N,S-codoped CNDs, 8, 5, and 5 pathways were detected when exposed to concentrations of LC50, LC50/2, and LC50/4, respectively. In all cases, certain metabolic pathways were altered while others were either down-regulated or up-regulated. Some of these changes include the activation of alanine, aspartate, and glutamate metabolism, aminoacyl-tRNA biosynthesis, butanoate metabolism, D-glutamine, and D-glutamate metabolism, glutathione metabolism, selenoamino acid metabolism, valine, leucine, and isoleucine degradation pathways. Moreover, the deactivation of starch and sucrose metabolism, the glycine, serine, and threonine metabolism, among others, were recorded. Our findings underline the importance to further study the impact of CNDs on marine organisms. As zebrafish has been shown to share many similarities with humans in bioprocesses and genome, it can be assumed that CNDs may also pose a threat to human health.

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Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury

Cited by 13 publications

References 42 publications

Use of Zebrafish in Drug Discovery Toxicology

Use of Zebrafish in Drug Discovery Toxicology

Parallel Reaction Monitoring reveals structure-specific ceramide alterations in the zebrafish

Metabolomic Profiling Unveils the Impact of Non-Doped and Heteroatom-Doped Carbon Nanodots on Zebrafish (Danio rerio) Embryos

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