Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity

Abstract

Chemically-induced vascular toxicity during embryonic development may cause a wide range of adverse effects. To identify putative vascular disrupting chemicals (pVDCs), a predictive pVDC signature was constructed from 124 U.S. EPA ToxCast high-throughput screening (HTS) assays and used to rank 1060 chemicals for their potential to disrupt vascular development. Thirty-seven compounds were selected for targeted testing in transgenic Tg(kdrl:EGFP) and Tg(fli1:EGFP) zebrafish embryos to identify chemicals that impair developmental angiogenesis. We hypothesized that zebrafish angiogenesis toxicity data would correlate with human cell-based and cell-free in vitro HTS ToxCast data. Univariate statistical associations used to filter HTS data based on correlations with zebrafish angiogenic inhibition in vivo revealed 132 total significant associations, 33 of which were already captured in the pVDC signature, and 689 non-significant assay associations. Correlated assays were enriched in cytokine and extracellular matrix pathways. Taken together, the findings indicate the utility of zebrafish assays to evaluate an HTS-based predictive toxicity signature and also provide an experimental basis for expansion of the pVDC signature with novel HTS assays.

Beyond organoids: In vitro vasculogenesis and angiogenesis using cells from mammals and zebrafish

“…In this line, GFP is specifically expressed in endothelial cells under the control of the VEGFR2 or kdr-like gene [204]. The kdrl:GFP line allows high resolution analysis of single cell migration and vascular development in living embryos [204].The utility of kdrl:GFP zebrafish embryos has been confirmed as a high-throughput model for screening the effect of toxic compounds on vascular development [205].…”

Assaying uptake of endocrine disruptor compounds in zebrafish embryos and larvae

“…Aquatic animal models, such as zebrafish, are used to study the environmental impact of EEDs. One common approach is to expose zebrafish embryos to known and suspected EEDs and assay their toxicity (Bouwmeester et al, 2016; Carroll et al, 2014; Gorelick et al, 2014; Padilla et al, 2012; Tal et al, 2016). However, for the majority of EEDs, information regarding the precise uptake and excretion is lacking.…”

Blood‐brain barrier development: Systems modeling and predictive toxicology

“…Zebrafish share protein sequence homology for many of the key receptors implicated in BBB development (Figure ), and use of this model facilitates reduction of the number of animals used in toxicity research (Perkins et al, ). Moreover, a recently developed transgenic zebrafish that expresses fluorescent GLUT1 as a marker of the BBB (Umans et al, ) could be used to screen for putative BBB disrupting chemicals similar to the approach that was used by Tal et al () to identify angiogenesis inhibitors from the ToxCast library (Tal et al, ). Furthermore, this model also offers in vivo visualization (e.g.…”