Zebrafish embryos as an alternative model for screening of drug-induced organ toxicity

Abstract

Zebrafish have initially emerged as model in developmental biology. The ease of maintenance, high number of offspring, transparency of the eggs and its suitability in mutagenicity screens to unravel developmental pathways contributed to its popularity. Today, it can be considered as one of the best characterised vertebrate models and more than 1,000 labs worldwide use the zebrafish (Strahle et al. 2012). At around 1990 zebrafish were discovered also as a toxicology model (Gorge and Nagel 1990), and the popularity is still increasing (Busch et al. 2011). A major reason for the attractiveness of this small teleost is associated with the suitability of its embryonic life stages. Early life stages are considered to sentinel no or less pain or discomfort when exposed to chemicals. Hence, according to European regulation (EU 2010), they are accepted as alternatives to animal experiments (Embry et al. 2010; Halder et al. 2010). Furthermore, the zebrafish embryo model has the principal capacity of high-throughput analysis and can be used in, for example, screenings for low toxicity of drug candidates. Zebrafish embryos provide an enormous versatility of applications in both environmental and human hazard assessment ranging from acute systemic toxicity (Ali et al. 2011; Lammer et al. 2009; Padilla et al. 2012), chronic toxicity (Volz et al. 2011), teratogenicity (Gustafson et al. 2012; Selderslaghs et al. 2009), neuractivity/neurotoxicity (Kokel et al. 2010; Selderslaghs et al. 2010), and endocrine disruption (Brion et al. 2012; Thienpont et al. 2011) to specific organ toxicities (Berghmans et al. 2008; Parng et al. 2002). As outlined by the paper of Driessen et al. in this issue of Archives in toxicology, hepatotoxicity is one of the major concerns of organ toxicity in drug development. Identification of hepatoxicity as early as possible in the drug development pipeline would reduce the costs associated with development of new medicines. Traditional animal models are time and cost intensive and subject to ethical concerns. Genuine cell-based in vitro methods do not provide the complexity of animal models and may provide only limited predictivity. Therefore, the zebrafish embryo has been proposed also as a better model to identify organ toxicity. As shown by Driessen et al., zebrafish embryos can indeed be used to identify hepatotoxicity. However, it is important to translate the observations appropriately, since histopathological effects or individual gene responses may differ among vertebrates. Identification of key events and conserved mechanisms can be supported by toxicogenomic analysis, and hence, it is not surprising that the number of studies in zebrafish embryos supported or accompanied by toxicogenomic analysis is increasing (e.g. Buttner et al. 2012; Hermsen et al. 2012; Pelayo et al. 2012; Schiller et al. 2012; Yang et al. 2007). Transcriptional profiling of whole embryos is even able to reveal organ-specific profiles—as shown in the Driessen paper in this issue and by various other studies (e.g. Kluver et al. 2011; Yang et al. 2007). With the advent of next generation sequencing (NGS), new perspectives for transcriptome profiling by RNA-sequencing (RNA-seq) are provided also for the zebrafish embryo model (Aanes et al. 2011; Vesterlund et al. 2011). With RNA-seq, novel transcripts from annotated or non-annotated regions not available in predefined probe sets, alternative splicing forms and rare transcripts can be detected. This could be important for the comparative analysis and identification of conserved key toxicity pathways in vertebrates. At present, S. Scholz (&) Department of Bioanalytical Ecotoxicology, UFZ Helmholtz Centre for Environmental Research, Permoserstr. 15, 04318 Leipzig, Germany e-mail: Stefan.Scholz@ufz.de