Zebrafish for drug toxicity screening: Bridging the in vitro cell-based models and in vivo mammalian models
ABSTRACT INTRODUCTION: Over the past decade, zebrafish have been tasked to play important roles from modeling human diseases to finding cures for them. Inadvertently, these fish now find themselves swimming along the drug development pipeline. A number of studies have been conducted to see if these small fish are up to the task of drug toxicity testing, an important rite of passage along the pharmaceutical pipeline. AREAS COVERED: This review covers the recent publications (2008 - 2010) on the state-of-the-art applications that couple advanced technologies with the unique advantages of zebrafish for drug toxicity screening. The paper looks at the several automated high-throughput platforms that have been developed for zebrafish teratogenicity, cardiotoxicity and neuro-sensory organ toxicity assays over the past 3 years as well as the important studies related to metabolism and biotransformation of selected drugs that have been initiated. This paper also reviews their mechanistic and predictive omics applications. EXPERT OPINION: While there have been a number of developments over the past 3 years and indeed over the last 10 years, challenges and limitations still exist, which, unless overcome, will prevent zebrafish from truly reaching their full potential as a drug toxicological model. That being said, recent developments have suggested that zebrafish could play a role in bridging the gap between in vitro cell-based models and in vivo mammalian models.
- SourceAvailable from: Andre Wolterbeek
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- "An alternative approach is the use of the whole liver system of zebrafish larvae, with unique advantages for early medium throughput in vivo toxicity screening that can precede preclinical toxicity testing. Zebrafish larvae are only 1–4 mm long and can live in a single well of a 96-well plate for several days (Sukardi et al., 2011). "
ABSTRACT: Drug-induced liver injury (DILI) is poorly predicted by single-cell-based assays, probably because of the lack of physiological interactions with other cells within the liver. An intact whole liver system such as one present in zebrafish larvae could provide added value in a screening strategy for DILI; however, the possible occurrence of other organ toxicities and the immature larval stage of the zebrafish might complicate accurate and fast analysis. We investigated whether expression analysis of liver-specific fatty acid binding protein 10a (lfabp10a) was an appropriate endpoint for assessing hepatotoxic effects in zebrafish larvae. It was found that expression analysis of lfabp10a was a valid marker, as after treatment with hepatotoxicants, dose-response curves could be obtained and statistically significant abnormal lfabp10 expression levels correlated with hepatocellular histopathological changes in the liver. However, toxicity in other vital organs such as the heart could impact liver outgrowth and thus had to be assessed concurrently. Whether zebrafish larvae were suitable for assessing human relevant drug-induced hepatotoxicity was assessed with hepatotoxicants and non-hepatotoxicants that have been marketed for human use and classified according to their mechanism of toxicity. The zebrafish larva showed promising predictivity towards a number of mechanisms and was capable of distinguishing between hepatotoxic and non-hepatotoxic chemical analogues, thus implying its applicability as a potential screening model for DILI. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.Journal of Applied Toxicology 02/2015; 35(9). DOI:10.1002/jat.3091 · 2.98 Impact Factor
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- "These studies, while sporadic in nature, underscored a neglected understanding of the ADME profile of drugs between zebrafish and human or other mammalian models which is affected by factors such as the route of administration and physiology of the fish. To fully realize the potential of zebrafish as a drug toxicological model, the knowledge gap in ADME needs to be addressed (Sukardi et al., 2011). Recently, the intra-peritoneal route of administration was used for optimization of the zebrafish model for cardiovascular safety assessment (Chaudhari et al., 2013). "
ABSTRACT: Early assessment of the toxicity potential of new molecules in pharmaceutical industry is a multi-dimensional task involving predictive systems and screening approaches to aid in the optimization of lead compounds prior to their entry into development phase. Due to the high attrition rate in the pharma industry in last few years, it has become imperative for the nonclinical toxicologist to focus on novel approaches which could be helpful for early screening of drug candidates. The need is that the toxicologists should change their classical approach to a more investigative approach. This review discusses the developments that allow toxicologists to anticipate safety problems and plan ways to address them earlier than ever before. This includes progress in the field of in vitro models, surrogate models, molecular toxicology, 'omics' technologies, translational safety biomarkers, stem-cell based assays and preclinical imaging. The traditional boundaries between teams focusing on efficacy/ safety and preclinical/ clinical aspects in the pharma industry are disappearing, and translational research-centric organizations with a focused vision of bringing drugs forward safely and rapidly are emerging. Today's toxicologist should collaborate with medicinal chemists, pharmacologists, and clinicians and these value-adding contributions will change traditional toxicologists from side-effect identifiers to drug development enablers. Copyright © 2013 John Wiley & Sons, Ltd.Journal of Applied Toxicology 06/2014; 34(6):576-94. DOI:10.1002/jat.2935 · 2.98 Impact Factor
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- "Relevance and predictability of drug response between zebrafish and human have been studied, and it has been found that zebrafish show a high percentage of predictability (78% and 70%) of drug response (Hung et al., 2012; Sukardi et al., 2011). The zebrafish heart, which begins beating within 26 h postfertilization (hpf) and looping by 48 hpf, is encased by a pericardial sac in the thoracic cavity below the pectoral bone and the atrium, which is medially dorsal and posterior to the ventricle (Bakkers, 2011), provides an easy-handling, low-cost and high-throughput system to observe heart rate and structure change and to perform gene alteration assays. "
ABSTRACT: Drug-induced cardiotoxicity is a leading factor for drug withdrawals, and limits drug efficacy and clinical use. Therefore, new alternative animal models and methods for drug safety evaluation have been given great attention. Anthracyclines (ANTs) are widely prescribed anticancer agents that have a cumulative dose relationship with cardiotoxicity. We performed experiments to study the toxicity of ANTs in early developing zebrafish embryos, especially their effects on the heart. LC50 values for daunorubicin, pirarubicin, doxorubicin (DOX), epirubicin and DOX-liposome at 72 h post-fertilization were 122.7 μM, 111.9 μM, 31.2 μM, 108.3 μM and 55.8 μM, respectively. At the same time, zebrafish embryos were exposed to ANTs in three exposure stages and induced incomplete looping of the heart tube, pericardia edema and bradycardia in a dose-dependent manner, eventually leading to death. DOX caused the greatest heart defects in the treatment stages and its liposome reduced the effects on the heart, while daunorubicin produced the least toxicity. Genes and proteins related to heart development were also identified to be sensitive to ANT exposure and downregulated by ANTs. It revealed ANTs could disturb the heart formation and development. ANTs induced cardiotoxicity in zebrafish has similar effects in mammalian models, indicating that zebrafish may have a potential value for assessment of drug-induced developmental cardiotoxicity. Copyright © 2014 John Wiley & Sons, Ltd.Journal of Applied Toxicology 05/2014; 35(3). DOI:10.1002/jat.3007 · 2.98 Impact Factor