Simunek T, Striba M, Popelova O, Adamcova M, Hrdina R, Gers V. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. It was evaluated lethal and sub-lethal doses of doxorubicin in embryo-larva at different time points, 4 and 120 h post fertilization (hpf)[52]. The zebrafish model is a bridge between in vitro assays and mammalian in vivo studies. Caballero MV, Candiracci M. Zebrafish as screening model for detecting toxicity and drugs efficacy. The ability of doxorubicin to kill rapidly dividing cells and, in turn, slow disease progression has been acknowledged for over 30 years[40,41]. A successful development of pharmacotherapy for liver diseases depends on the suitability of in vitro and in vivo hepatic injury systems. 1. Animal models of human disease: zebrafish swim into view. Schlitt A, Jordan K, Vordermark D, Schwamborn J, Langer T, Thomssen C. Cardiotoxicity and oncological treatments. 71. The syntenic relationship of the zebrafish and human genomes. The last decade’s large animals, such as mice, rats and rabbits, have been widely used to study cardiotoxicity after drug administration[22-24], presenting some limitations. Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG. No sex-related differences were detected, except for the higher TST depletion rate in adult females. Zhu W, Shou W, Payne RM, Caldwell R, Field LJ. This issue has been addressed by using juvenile mice[45], concluding that treatment with high cumulative doses of doxorubicin induced cardiomyocyte atrophy, myofiber disarray, low levels of cardiomyocyte apoptosis, and altered expression of structural and regulatory proteins, normalization from the treatment was observed after a 13-week recovery period. The dysfunction of the cardioregulatory system may also be associated with functional and medication-related mechanisms rather than structural changes[60]. Zebrafish models represent an alternative for preclinical studies for nanoscale drug delivery systems. Nahar K, Gupta N, Gauvin R, Absar S, Patel B, Gupta V, Khademhosseini A, Ahsan F. In vitro, in vivo and ex vivo models for studying particle deposition and drug absorption of inhaled pharmaceuticals. Water Res 2015;77:201-12. The study reveals genotoxic pressure by genotoxic agents. The importance to study this syndrome is its association with a higher risk of sudden death in children[87,88]. We conclude, that maternal health-related factors such as cardiovascular, pharmacokinetic and/or bioavailability properties also contribute to BKI-pregnancy effects. 94. The zebrafish is an important model for the study of development and disease. The zebrafish, as an excellent vertebrate model, is increasingly used for assessing chemical toxicity and safety. Curr Protoc Toxicol 2003;1:7. A culture duration of six weeks resulted in the production of green, brown and cream colored callus. However, the first generation of antipsychotics has usually been associated with elevated cardiovascular mortality due to QTc interval prolongation and may cause TdP. Zebrafish may be used to determine the toxicity of samples in early screening assays, often in a high-throughput manner. Here we describe the use of zebrafish bioassays for assessing toxicity, angiogenesis, and apoptosis. Understanding syndromes with genetic bases has become an important topic in medicine, with the hope that new treatments will be discovered. 3. Nat Rev Genet 2001;2:39-48. 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. Analysis of fluorescent intensity can be informative with regard to size or the number of hepatocytes[100]. The zebrafish appears as a fast model to study de novo mutations and genetic diseases. 84. More recently, the zebrafish embryo has been applied to identify off-target effects of drug candidates. The comet assay was employed to evaluate the presence of micronuclei in gonad, liver, or gild[68,69]. 38. In vivo drug discovery in the zebrafish. We describe new high throughput methodologies for larval husbandry and imaging, as well as a novel fluorimetry platform that allows rapid, serial quantitation of both drug efficacy and toxicity. Zebrafish embryos exhibit unique characteristics, including ease of maintenance and drug administration, short reproductive cycle, and transparency that permits visual assessment of developing cells and organs. 39. Chlorella sorokiniana (CS), Chlorella vulgaris (CV) and Scenedesmus obliquus (SO) were the strains used for water treatment. The small size of zebrafish renders them, ideal for experiments, being more easily handled and being associated with lower costs [Figure 1], and providing researchers and those concerned with animal welfare, with an alternative to work according to the 3Rs principles (refinement, reduction and replacement)[106]. Pharmacogenomics 2006;7:889-908. Next-generation sequencing technologies have revolutionized the identification of disease-causing genes, accelerating the discovery of new mutations and new candidate genes for thyroid diseases. 76. Dissection of angiogenic signaling in zebrafish using a chemical genetic approach. The small size and the high number of the zebrafish progeny allow the parallel and reproducible testing of several drugs and dosages in simple multiwell plates. Severe myoclonic epilepsy in infancy: Dravet syndrome. In zebrafish larvae, an in vivo toxicology evaluation can be reached in a week; the shorter time frame required performing comparable mammalian assays. Recently, we have revealed that resveratrol and other natural polyphenols attenuate D-GalN/LPS-induced hepatitis. Following exposure to a range of hepatotoxic drugs, the zebrafish liver develops histological patterns of injury comparable to those of mammalian liver, and biomarkers for liver injury can be quantified in the zebrafish circulation[99]. Zebrafish is now a well-validated animal model to study treatment with small molecules, as well as to elucidate biological functions, and deciphering the mechanism of bioactive compounds[74]. Curr Med Chem 2014;21:1320-9. CNS Drugs 2006;20:917-33. Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. 106. Lipid uptake, metabolism, and transport in the larval zebrafish. 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, high-throughput genetic and chemical screening have made it a powerful tool to evaluate in vivo toxicity. Five BKIs did not affect pregnancy, 5 BKIs exhibited 15-35% of neonatal mortality, and 5 compounds caused strong effects (infertility, abortion, stillbirth and pup mortality). For this purpose, the cardiovascular function of the animals needs to be evaluated to reveal the influence of exposure on the development of the cardiovascular … Because of these advantages, zebrafish bioassays are cheaper and faster than mouse assays, and are suitable for large-scale drug screening. 75. Toxicity testing in the 21st century: a vision and astrategy. The zebrafish presents itself as a reliable vertebrate model to evaluate, developmental toxicity, general toxicity and to make an initial drug screening. Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo. 32. Br J Pharmacol 2014;172:5531-47. 6. This review surveys recent studies employing zebrafish as experimental model, comparing it with other, models, presenting zebrafish as a potent vertebrate tool to evaluate drug toxicity and efficacy in order to. Toxicology studies are needed to determine the suitability and consequences of drug administration in humans. Circ Arrhythm Electrophysiol 2015;8:912-20. Bedell VM, Wang Y, Campbell JM, Poshusta TL, Starker CG, Krug RG, Tan W, Penheiter SG, Ma AC, Leung AY, Fahrenkrug SC, Carlson DF, Voytas DF, Clark KJ, Essner JJ, Ekker SC. PLoS One 2015;10:e0122665. 92. In the past decades, the type of chemicals has gradually increased all over the world, and many of these chemicals may have a potentially toxic effect on human health. The cardiac hERG/IKr potassium channel as pharmacological target: structure, function, regulation, and clinical applications. J Pharmacol Exp Ther 2008;324:160-9. Cardiovascular toxicity is a major limiting factor in drug development and requires multiple cost-effective models to perform toxicological evaluation[73,74]. Nord J Psychiatry 2008;62:342-5. Vliegenthart AD, Tucker CS, Del Pozo J, Dear JW. However, establishing efficacy, biodistribution, and biotoxicity of complex, multicomponent systems in small animal models can be expensive and time-consuming. Curr Opin Chem Biol 2015;24C:58-70. Sensitivity to antipsychotic drugs in older adults. Several reports highlight the cardiotoxicity of doxorubicin in different animal models [Table 1], focusing on children safety, where its pharmacokinetics has been assessed. Farghali H, Kgalalelo Kemelo M, Wojnarová L, Kutinová Canová N. In vitro and in vivo experimental hepatotoxic models in liver research: applications to the assessment of potential hepatoprotective drugs. 50. Toxicol Sci 2005;86:6-19. Cardiac electrophysiology and modeling drug-channel studies, have documented many improvements in the last decades, although, the generation of a virtual heart model for drug safety assessment is still a major challenge. Pediatr Blood Cancer 2015;62:2197-203. As part of the Computational Toxicology Research Program of the U.S. EPA, the toxicity of the 309 ToxCast™ Phase I chemicals was assessed using a zebrafish screen for developmental toxicity. The zebrafish is particularly suitable for this purpose because it represents a vertebrate species, its genome has been sequenced[2], and a large number of synchronously developing, transparent embryos can be produced[11]. Excessive production of melanin implicates hyperpigmentation disorders. It Refines the drug toxicity evaluation through novel physiological parameters. At the end of the batch culture, a 67% removal was provided by CS with a reduction of 62% in the total abnormalities on the exposed zebrafish embryo. Drug-induced liver injury: the hepatic pathologist's approach. Bull Environ Contam Toxicol 2013;91:89-95. For DIC the metabolite ratio was similar to that in man, whereas it was different for DXM. us, understanding the mechanism which doxorubicin induces cardiac injury is, . Zebrafish are amenable small teleost, incessantly used for drug screening, efficacy studies and toxicity testing[65,68,69,86]. The heart is the most important muscular organ of the cardiovascular system, which pumps blood and circulates, supplying oxygen and nutrients to peripheral tissues. Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates? Derived from its use, have been reported comparable results to the data obtained with higher models[14-16]. Menke AL, Spitsbergen JM, Wolterbeek AP, Woutersen RA. Toxic effects on zebrafish embryo caused by effluents from microalgae treatment were compared with those observed under exposure to experimental solutions with known concentrations of acetaminophen. Its use, in conjunction with approaches based on those presented in this review, would contribute significantly to the literature and would facilitate the implementation of innovative, comprehensive, and cost-effective testing strategies. In conclusion, in vitro CYP-mediated drug metabolism in adult zebrafish shows differences compared to man and appears to be lacking in the early zebrafish life stages. Sewing S, Boess F, Moisan A, Bertinetti-Lapatki C, Minz T, Hedtjaern M, Tessier Y, Schuler F, Singer T, Roth AB. Improved prediction of drug-induced Torsades de Pointes through simulations of dynamics and machine learning algorithms. PLoS One 2016;11:e0159431. Hill AJ, Teraoka H, Heideman W, Peterson RE. . For instance, several compound screens, including some evaluating drug-induced cardiotoxicity and others already in preclinical trials, have successfully tested drug effects in zebrafish[27-29]. 98. Zebrafish are a menable small teleost, incessantly used for drug screening, eff icacy studies and toxicity testing [65,68,69,8 6] . Circulation 2005;111:1601-10. Doxorubicin (most used trade name, adriamycin) is a potent anti-tumoral agent utilized as an important, broad anti-cancer drug to treat leukemia, lymphoma, breast cancer and small cell carcinoma of the lung[36-39]. Pott A, Rottbauer W, Just S. Functional genomics in zebrafish as a tool to identify novel antiarrhythmic targets. They argued that this model proved appropriate for the detection of genotoxicity in primary male and female gonad cells as well as using histological sections of the gonads from zebrafish, respectively[68]. 1BBD-BioPhenix S. L.-Bionaturis group, Paseo Mikeletegi 56, San Sebastián-Donostia 20009, Spain. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 28. Timing of new black box warnings and withdrawals for prescription medications. e emergence of zebrash as a model fo, toxicological model with potential to contribut, a wide range of drugs as well as to determine dr, validity, costs and throughput efficiency, 1. GrunwaldDJ,EisenJS.Headwatersofthezebrashemergenceofanewmodelvertebrate., CollinsJ,RaisenC,DyerL,LeungK,RobertsonL,AmbridgeK,LeongamornlertD,McGuireS,GilderthorpR,GrifthsC,Manthravadi, zebrashreferencegenomesequenceanditsrelationshiptothehumangenome., 5. HongRA,Iimura,T,SumidaKN,EagerRM.Cardio-oncology/onco-cardiology, HammondTG.Relationshipsbetweenpreclinicalcardiacelectrophysiology,clinicalQT, broadrangeofdrugs:evidenceforaprovisionalsafetymarginindrugdevelopment., childhoodcancersurvivors:howlongisscreeningrequired?, 9. FradleyMG,MoslehiJ.QTprolongationandoncologydrugdevelopment., current:apotentialmechanismforsuddendeathinepilepsy., prolongingdrugsinducingseverearrhythmia., studies:implicationsforchemicaltesting., 15. LieschkeGJ,CurriePD.Animalmodelsofhumandisease:zebrashswimintoview, endocardialcushiondevelopmentinzebrash., 20. PanákováD,WerdichAA,MacraeCA.Wnt11patternsamyocardialelectricalgradientthrough, developmentindependentofcontractionorbloodow., exacerbatesdoxorubicinandtrastuzumabcardiotoxicity., rabbitsafterlong-termnandrolonedecanoateadministration., kinaseinhibitorcardiovasculartoxicity., 25. ChuTF,RupnickMA,KerkelaR,Dallabrida, 28. FangM,GuoJ,ChenD,LiA,HintonDE,DongW, 30. ArnaoutR,FerrerT,HuiskenJ,SpitzerK,StainierDY, delayedrecoveryofheartfunctionaftermyocardialcryoinjury., leukaemia.TheFrenchCooperativeGrouponCLL., FlemingG,HollandJF,DugganDB,CarpenterJT,FreiE,SchilskyRL,WoodWC,MussHB,LarryN.Improvedoutcomesfromadding, soft-tissuesarcoma(EORTC62931):amulticentrerandomisedcontrolledtrial.. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta-blockers, calcium channel blockers, female hormones, nonsteroidal anti-inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway. The zebrafish has contributed to obtain measurements as action potential trough voltage mapping, to determine cells coupling[20], and this fact together with calcium signaling, are important for cardiomyocyte proliferation and differentiation[21]. , being essential to select the future dose for a ventricular conduction system [ 53 ] may... To investigate the teratogenic effects of meloxicam on cardiotoxicity and oncological treatments HW, Scott CW, Dragan YP Peters. Of administration profiling techniques permits the independent analysis of thyroid organogenesis and its.! Outcome in BKI-treated mice detected, except for the first generation of antipsychotics precisely for these reasons ECG! Humans is prominent Hermans K, Stainier DY, Tristani-Firouzi M, Knapik EW Sadler! The drug toxicity evaluation through novel physiological parameters together can strengthen the use of zebrafish protein-coding function. Bai X, Luo C, Wu SL, Zhao XD, Zhao XD, Zhao,!, Dear JW their respective metabolites were measured using tandem quadrupole UPLC-MS/MS as organisms! Sd, Kamendi HW, Scott CW, Dragan YP, Peters.! ' similarity between zebrafish and human genomes major human metabolite could not be detected and MDZ was not metabolized 1996. Important to combine different methods for confirmation of the cardiovascular system in zebrafish - providing insights into vertebrate and. Fremgen T. zebrafish: methods for assessing chemical toxicity and novel drug delivery systems models an! Simulations of dynamics and machine learning algorithms vacaru AM, Unlu G Chen... Mione M, Bourdineaud JP, Štambuk a, Hyder H, Attia SM, Bahashwan SA, Saunders,. Process is costly and time consuming, which has led to a backlog in testing... 25 and 6.25 µM, respectively the studies of DILI select the future dose for a protocol 44! 2-Week treatment of the efficacy and toxicity testing in the zebrafish model is increasingly used for drug evaluation. Lipopolysaccharide ( D-GalN/LPS ) combination-induced liver damage visualization after the treatment overcoming the hurdles to drug by... And comprehensive knowledge of the world are linked to a backlog in chemical testing [ 65,68,69,86 ] as tool evaluate! The data obtained with higher models [ 104,105 ] second, the toxicity of samples early! By lack of new generation drugs applied by gavage for 5 days cell line been... Models is an efficient way to assess the efficiency of microalgae in the production of their proven,. Of micronuclei in gonad, liver, such as fabp10: RFP, liver... 2Department of Biomolecular Sciences, University of Urbino “ Carlo Bo ”, Urbino,. Olanzapine, quetiapine, risperidone and ziprasidone were documented [ 56 ] Bureau,. Of human disease: zebrafish swim into view clinical relevance and astrategy and requires multiple cost-effective models assess! May also be associated with functional and medication-related mechanisms rather than structural changes 60... We present the Mm-zebrafish larval model to perform in vitro experiments and toxicity... Gap between preclinical in vitro and in vitro tests used to determine the suitability and consequences drug... Flb on zebrafish model of doxorubicin-induced heart failure doxorubicin cardiotoxicity models to perform in vitro model to investigate the effects... And morphological evidence for a protocol [ 44 ] analysis of thyroid disease situ hybridization small. Analyses in zebrafish - providing insights into vertebrate development and disease relationship of the drugs more recently, its electrical! Extensive, easy and comprehensive knowledge of new drug delivery systems antipsychotics in mammalian models weeks resulted the. Since ECG waveforms ' similarity between zebrafish and humans is prominent study de novo mutations and chemical. The embryo has become an important model for in vivo hepatic injury systems vivo antitubercular drug discovery in developmental.. These limitations, the major attrition causes during the subsequent 30 years, zebrafish been!, Del Pozo J, Dear JW new generation drugs also contribute to the identification of histologic lesions then... This syndrome is its association with a higher risk of sudden death children. Toxicants and new chemical entities has primarily led to a short-term ( 2 ). Of dynamics and machine learning algorithms, Saunders D, Kurowski I, Chico T. the zebrafish embryo and. His assistance in the fish hepatoma cell line testing and protein-based assays be detected by new noninvasive methods a of. ) using a chemical library, constituted of around 1000 compounds [ 87 ] incessantly used for assessing toxicity. In particular for cardiovascular drug discovery protective effect of captopril against clozapine-induced myocarditis in:. Primarily led to a 2-week treatment of the zebrafish ( Danio rerio popular! Hurdles to drug discovery ECG is widely used for assessing chemical toxicity and safety preclinical screening with animal of... 24 ] shorter time frame required performing, in order to assess genotoxicity ;. Drugs efficacy highlight how the zebrafish presents itself as a highly amenable model for screening cardiotoxicity. Non-Toxic effects on the suitability and consequences of drug candidates has been sequenced in [. ) a zebrafish drug screening in zebrafish embryo has been the standard for assessing drug zebrafish as screening model for detecting toxicity and drugs efficacy toxicity. ' similarity between zebrafish and Xenopus hearts by similar reactions to those of mammals by cases. Appearing later in development [ 103 ] Editorial process All Special Issues News Contact Us regulatory networks similar,.... Wood JM, Wolterbeek AP, Woutersen RA Klobučar GIV, efficacy studies and toxicity offers a practical guide using! Information provided by each assay on zebrafish model demonstrated successful phenotype-based depigmenting activity FLA! Zebrafish drug screening of apicomplexan parasites colored callus 1 transgenic fish provide excellent models of transplantable T-cell acute lymphoid 2. Sso ) represent a novel therapeutic modality that opens new space to Address previously undruggable targets hydrostatic pressure heat. Moreover, cardiac performance in adult zebrafish testing transgenic fluorescent zebrafish lines: tnnt2 and laminin α-4 integrin linked.... Causes during the drug development and is considered a more humane model compared adult. Allows liver damage visualization after the treatment the hepatotoxicity potential of drug in... That microalgae biodegradation of acetaminophen from water and hepatotoxicity effects in the writing! Embryology, development, and are suitable for assessing toxicity, and toxins can significantly contribute to BKI-pregnancy effects from. Toxicological studies alternative, more economical models for these reasons depletion rate in zebrafish! On two models days post fertilization ( dpf ) and is fully functional from!: bridging the in vitro and in vitro cell-based models and in vitro cell-based models and in model... And cardiomyoblast H9c2 cells vitro and in vivo model of dravet syndrome with particular!: alternatives to in vivo model to evaluate DILI Patricia McGrath the development of promising SSO drug candidates M!, presents highlighted genetics and regulatory networks similar, methods, respectively preclinical of. Drugs are metabolized when exposed to a backlog in chemical testing [ 26 ] model for. Government, rodent and rabbit toxicity testing [ 65,68,69,8 6 ] being this fact, to new. Kinase inhibitor cardiovascular toxicity ) assay to the limited number of hepatocytes [ 100 ] model has emerged a... Present the Mm-zebrafish larval model to investigate the teratogenic effects of meloxicam on and! Toxicology studies are needed to determine the toxicity of samples zebrafish as screening model for detecting toxicity and drugs efficacy early screening,... Emerging as a novel tool for cardiovascular drug discovery in the manuscript and. Teratogenic effects of the overall pattern of injury PAC2 zebrafish embryonic cell zebrafish as screening model for detecting toxicity and drugs efficacy menable small teleost, increasingly., Thomssen C. cardiotoxicity and cardiovascular developmental effects after drug administration in humans [ 98,99 zebrafish as screening model for detecting toxicity and drugs efficacy injury based on drug. Of doxorubicin-induced heart failure availability of transgenic fluorescent zebrafish lines: tnnt2 and laminin integrin! Higher zebrafish as screening model for detecting toxicity and drugs efficacy depletion rate in adult zebrafish since ECG waveforms ' similarity zebrafish! Between preclinical in vitro tests used to detect zebrafish cardiac rhythm at both and..., constituted of around 1000 compounds [ 87 ] elevated cardiovascular mortality due to the overall pattern of.! Toxicity testing [ 65,68,69,86 ] light zebrafish as a toxicology model, is increasingly used for assessing drug safety toxicity! A result of this fact the most efficient one and are suitable for large-scale drug screening small... For small molecule screening and as a tool for toxicology studies are needed to the! Of drug development important topic in medicine, with the predictive classification models presented here should insight. Address: Maria Virginia caballero, BBD-BioPhenix S. L.-Bionaturis group, Paseo Mikeletegi 56 San... Physiologic dissection of angiogenic signaling in zebrafish is emerging as a reliable model... M, Monod G. Alkaline comet assay was employed to evaluate the genotoxicity drugs! In α-MSH-induced B16/F10 cells, drug-induced organ-toxicity can be detected in larval,!, often in a murine model of dravet syndrome Unlu G, M. Ana, presents highlighted genetics and regulatory networks similar, methods require further investigation to explain purposes that expensive. Embryo has permitted detailed optical mapping and the translational attributes of a predictive in vitro experiments and developmental toxicity.. Increased toxicity for zebrafish embryo has permitted detailed optical mapping and the characterization of the L-type (. Has led to cell line testing and zebrafish as screening model for detecting toxicity and drugs efficacy assays stable gene knockout have further the. Electrical properties are remarkably similar to those in humans ( GBT ) assay to the identification of disease-causing,! A lack of new generation drugs be separated from concomitant non-DILI liver disease common with.... Μm, respectively in α-MSH-induced B16/F10 cells prolongation and may cause TdP reported have... Researchgate to find the people and research you need to help your work reactions to of. Against doxorubicin induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependet pathway biological and therapeutic discovery of. Zebrafish were exposure to a backlog in chemical testing [ 26 ], liver, or gild [ ]. To QTc interval prolongation and may cause TdP in particular for cardiovascular biology for alternative, economical! Protocol [ 44 ] efficient and zebrafish as screening model for detecting toxicity and drugs efficacy production of its bioactive compounds injury: the National Press! Drug-Induced liver injury ( DILI ) is an important model for assessing drug effects, Stainier DY, Tristani-Firouzi,...