A multi-endpoint in vivo larval zebrafish (Danio rerio) model for the assessment of integrated cardiovascular function

Parker, Thomas S.; Libourel, Paul-Antoine; Hetheridge, Malcolm J.; Cumming, Robert I.; Sutcliffe, Thomas P.; Goonesinghe, Alexander; Ball, Jonathan S.; Owen, Stewart F.; Chomis, Yann; Winter, Matthew J.

doi:10.1016/j.vascn.2013.10.002

Cited by 65 publications

(80 citation statements)

References 31 publications

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“…Heart rate in larval Betta and Trichopodus was~160 and~210 beats/min, respectively. Relatively few measurements of heart rate exist for the larvae of either air breathing or strictly aquatic species, but the rates recorded in this study are within the range of those recorded at similar temperatures (27-28̊°C) in another larval air-breathing fish, the tropical gar Atractosteus tropicus (Burggren et al 2016) and in unrestrained, larval zebrafish (Danio rerio), for example, (Barrionuevo and Burggren 1999;Jacob et al 2002;Kopp et al 2014;Miller et al 2014;Parker et al 2014;Rider et al 2012;Rombough 2007;Steele et al 2011;Velasco-Santamaria et al 2011). In this respect, the earliest strictly aquatic stages of these air-breathing fishes physiologically resemble those of aquatic freshwater fishes, generally.…”

Section: Development In Normoxiasupporting

confidence: 68%

Cardiorespiratory physiological phenotypic plasticity in developing air‐breathing anabantid fishes ( Betta splendens and Trichopodus trichopterus )

Méndez-Sánchez

Burggren

2017

Physiol Rep

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Developmental plasticity of cardiorespiratory physiology in response to chronic hypoxia is poorly understood in larval fishes, especially larval air‐breathing fishes, which eventually in their development can at least partially “escape” hypoxia through air breathing. Whether the development air breathing makes these larval fishes less or more developmentally plastic than strictly water breathing larval fishes remains unknown. Consequently, developmental plasticity of cardiorespiratory physiology was determined in two air‐breathing anabantid fishes (Betta splendens and Trichopodus trichopterus). Larvae of both species experienced an hypoxic exposure that mimicked their natural environmental conditions, namely chronic nocturnal hypoxia (12 h at 17 kPa or 14 kPa), with a daily return to diurnal normoxia. Chronic hypoxic exposures were made from hatching through 35 days postfertilization, and opercular and heart rates measured as development progressed. Opercular and heart rates in normoxia were not affected by chronic nocturnal hypoxic. However, routine oxygen consumption M˙normalO2 (~4 μmol·O2/g per hour in normoxia in larval Betta) was significantly elevated by chronic nocturnal hypoxia at 17 kPa but not by more severe (14 kPa) nocturnal hypoxia. Routine M˙normalO2 in Trichopodus (6–7 μmol·O2/g per hour), significantly higher than in Betta, was unaffected by either level of chronic hypoxia. P Crit, the PO2 at which M˙normalO2 decreases as ambient PO2 falls, was measured at 35 dpf, and decreased with increasing chronic hypoxia in Betta, indicating a large, relatively plastic hypoxic tolerance. However, in contrast, P Crit in Trichopodus increased as rearing conditions grew more hypoxic, suggesting that hypoxic acclimation led to lowered hypoxic resistance. Species‐specific differences in larval physiological developmental plasticity thus emerge between the relatively closely related Betta and Trichopodus. Hypoxic rearing increased hypoxic tolerance in Betta, which inhabits temporary ponds with nocturnal hypoxia. Trichopodus, inhabiting more permanent oxygenated bodies of water, showed few responses to hypoxia, reflecting a lower degree of developmental phenotypic plasticity.

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Section: Development In Normoxiasupporting

confidence: 68%

Cardiorespiratory physiological phenotypic plasticity in developing air‐breathing anabantid fishes ( Betta splendens and Trichopodus trichopterus )

Méndez-Sánchez

Burggren

2017

Physiol Rep

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“…The four selected control drugs have been selected due to their reported toxicities both in humans and zebrafish. Haloperidol, a known anti-dopaminergic antipsychotic drug, has been used as our positive cardiotoxic drug because it has been described to produce hERG blockade, QT interval prolongation, and arrhythmias both in humans and zebrafish [19,20,21]. MPTP, a prodrug to 1-methyl-4-phenylpyridinium (MPP + ) first synthesized as an analgesic, has been shown to cause permanent Parkinson’s symptoms by destroying dopaminergic neurons in the substantia nigra [22].…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown the relevance of using zebrafish for predicting the possible impact of drugs in those three organs individually [21,29,50,51,52,53,54,55,56]. However, no previous studies have integrated the analysis of these three organ-toxicities in the same animal; a procedure that reduces animal usage, experimental time and costs, and the quantity of the tested compound.…”

Section: Discussionmentioning

confidence: 99%

“…For every compound, a no observed effect concentration (NOEC) was identified to use in the following experiments. The concentrations for drugs used as organo-toxic positive controls were obtained from previous publications and in-house validation: paracetamol (2600 µM; [46]), EtOH (2%; [26]), MPTP (100 µM; [30]), and haloperidol (10 µM; [21]). DMSO 1% was used as the negative control in all experiments.…”

Section: Methodsmentioning

confidence: 99%

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ZeGlobalTox: An Innovative Approach to Address Organ Drug Toxicity Using Zebrafish

Cornet

Calzolari

Minana-Prieto

et al. 2017

IJMS

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Toxicity is one of the major attrition causes during the drug development process. In that line, cardio-, neuro-, and hepatotoxicities are among the main reasons behind the retirement of drugs in clinical phases and post market withdrawal. Zebrafish exploitation in high-throughput drug screening is becoming an important tool to assess the toxicity and efficacy of novel drugs. This animal model has, from early developmental stages, fully functional organs from a physiological point of view. Thus, drug-induced organ-toxicity can be detected in larval stages, allowing a high predictive power on possible human drug-induced liabilities. Hence, zebrafish can bridge the gap between preclinical in vitro safety assays and rodent models in a fast and cost-effective manner. ZeGlobalTox is an innovative assay that sequentially integrates in vivo cardio-, neuro-, and hepatotoxicity assessment in the same animal, thus impacting strongly in the 3Rs principles. It Reduces, by up to a third, the number of animals required to assess toxicity in those organs. It Refines the drug toxicity evaluation through novel physiological parameters. Finally, it might allow the Replacement of classical species, such as rodents and larger mammals, thanks to its high predictivity (Specificity: 89%, Sensitivity: 68% and Accuracy: 78%).

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“…Work by us (Brette et al, 2008) and others (Nemtsas et al, 2010;Verkerk and Remme, 2012;Bovo et al, 2013) clearly shows that the ZF heart is a relevant model for human cardiac ion channel disorders, particularly those associated with cardiac repolarisation. ZF are also an established model species for environmental and (eco) toxicology testing (Strähle et al, 2011;Busch et al, 2011), with recent work focusing on the effect of pollutants on the ZF cardiovascular system (Parker et al, 2014). Thus, we believe this novel in vitro system has promise for toxicology, disease modelling, understanding in vitro maturation, and tissue engineering.…”

Section: Introductionmentioning

confidence: 97%

Generating an In Vitro 3D Cell Culture Model from Zebrafish Larvae for Heart Research

Grunow

Mohamet

Shiels

2015

Journal of Experimental Biology

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We describe here a novel, fast and inexpensive method for producing a 3D 'heart' structure that forms spontaneously, in vitro, from larval zebrafish (ZF). We have named these 3D 'heart' structures 'zebrafish heart aggregate(s)' (ZFHAs) and have characterised their basic morphology and structural composition using histology, immunohistochemistry, electron microscopy and mass spectrometry. After 2 days in culture, the ZFHA spontaneously form and become a stable contractile syncytium consisting of cardiac tissue derived by in vitro maturation, which beats rhythmically and consistently for more than 8 days. We propose this model as a platform technology, which can be developed further to study in vitro cardiac maturation, regeneration, tissue engineering and safety pharmacological/toxicology testing.

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A multi-endpoint in vivo larval zebrafish (Danio rerio) model for the assessment of integrated cardiovascular function

Cited by 65 publications

References 31 publications

Cardiorespiratory physiological phenotypic plasticity in developing air‐breathing anabantid fishes ( Betta splendens and Trichopodus trichopterus )

Cardiorespiratory physiological phenotypic plasticity in developing air‐breathing anabantid fishes ( Betta splendens and Trichopodus trichopterus )

ZeGlobalTox: An Innovative Approach to Address Organ Drug Toxicity Using Zebrafish

Generating an In Vitro 3D Cell Culture Model from Zebrafish Larvae for Heart Research

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