Inter-laboratory assessment of a harmonized zebrafish developmental toxicology assay – Progress report on phase I

Gustafson, Anne-Lee; Stedman, Donald B.; Ball, Jonathan S.; Hillegass, Jedd M.; Flood, Annette; Zhang, C.X.; Panzica-Kelly, Julie; Cao, J.; Coburn, Aleasha; Enright, Brian; Tornesi, M.B.; Hetheridge, Malcolm J.; Augustine-Rauch, Karen

doi:10.1016/j.reprotox.2011.12.004

Cited by 101 publications

(77 citation statements)

References 21 publications

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“…On the other hand, the vast majority of Tier-I hits (98%) had LogP values favoring water-to-embryo partitioning (LogP>0) and Tier-II hits clustered within a narrower range of LogP values relative to Tier-I hits, suggesting that a short (2-h) exposure biased hits to hydrophobic compounds within an optimal LogP range (LogP = ~2–5). Therefore, these results are consistent with other studies showing that compound bioactivity is not associated with compound size (for compounds ≤3000 g/mol) but, rather, tends to be dependent on compound hydrophobicity (LogP>0) and partitioning from water into zebrafish embryos (whether chorionated or not) over a specific exposure duration (de Koning et al, 2015; Gustafson et al, 2012; Pelka et al, 2017; Sachidanandan et al, 2008). Finally, the lack of structural similarity suggests that, similar to LogPs and molecular weights, 2D chemical structures do not have the potential to predict hits within our assay; however, it is important to note that this lack of predictability may be driven by the inherent chemical diversity of the LOPAC 1280 library.…”

Section: Discussionsupporting

confidence: 92%

Behavioral screening of the LOPAC1280 library in zebrafish embryos

Vliet

Volz

2017

Toxicology and Applied Pharmacology

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Spontaneous activity represents an early, primitive form of motor activity within zebrafish embryos, providing a potential readout for identification of neuroactive compounds. However, despite use as an endpoint in chemical screens around the world, the predictive power and limitations of assays relying on spontaneous activity remain unclear. Using an improved high-content screening assay that increased throughput from 384 to 3,072 wells per week, we screened a well-characterized library of 1,280 pharmacologically active compounds (LOPAC1280) – 612 of which target neurotransmission – to identify which targets are detected using spontaneous activity as a readout. Results from this screen revealed that (1) 8% of the LOPAC1280 library was biologically active; (2) spontaneous activity was affected by compounds spanning a broad array of targets; (3) only 4% of compounds targeting neurotransmission impacted spontaneous activity; and (4) hypoactivity was observed for 100% of hits detected, including those that exhibit opposing mechanisms of action for the same target. Therefore, while this assay was able to rapidly identify potent neuroactive chemicals, these data suggest that spontaneous activity may lack the ability to discriminate modes of action for compounds interfering with neurotransmission, an issue that may be due to systemic uptake following waterborne exposure, persistent control variation, and/or interference with non-neurotransmission-related mechanisms.

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Section: Discussionsupporting

confidence: 92%

Behavioral screening of the LOPAC1280 library in zebrafish embryos

Vliet

Volz

2017

Toxicology and Applied Pharmacology

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“…In 2009, an international group of pharmaceutical companies formed a consortium to develop a zebrafish development assay that could correctly classify a set of 10 teratogenic and 10 nonteratogenic compounds (Gustafson et al, 2012). The results of these toxicity tests were compared to mammalian data, and found to have an overall concordance of 60–70%.…”

Section: High-throughput Screening For Toxicity Studiesmentioning

confidence: 99%

“…This approach yielded 87% concordance with published in vitro teratogenicity data (Brannen et al, 2010). Improvements to this assay, including enzymatic removal of the chorion, repeating the assay with a distinct set of text compounds, and using various zebrafish strains, have been attempted to make a direct comparison between the chorion-on data published by the pharmaceutical company consortium and the chorion-off data to determine whether the presence of the chorion affected the sensitivity and specificity of the zebrafish embryo assay (Ball et al, 2014; Brannen et al, 2010; Gustafson et al, 2012; Panzica-Kelly, Zhang, & Augustine-Rauch, 2015). …”

Section: High-throughput Screening For Toxicity Studiesmentioning

confidence: 99%

Zebrafish in Toxicology and Environmental Health

Bambino

Chu

2017

Current Topics in Developmental Biology

307

152

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As manufacturing processes and development of new synthetic compounds increase to keep pace with the expanding global demand, environmental health, and the effects of toxicant exposure are emerging as critical public health concerns. Additionally, chemicals that naturally occur in the environment, such as metals, have profound effects on human and animal health. Many of these compounds are in the news: lead, arsenic, and endocrine disruptors such as bisphenol A have all been widely publicized as causing disease or damage to humans and wildlife in recent years. Despite the widespread appreciation that environmental toxins can be harmful, there is limited understanding of how many toxins cause disease. Zebrafish are at the forefront of toxicology research; this system has been widely used as a tool to detect toxins in water samples and to investigate the mechanisms of action of environmental toxins and their related diseases. The benefits of zebrafish for studying vertebrate development are equally useful for studying teratogens. Here, we review how zebrafish are being used both to detect the presence of some toxins as well as to identify how environmental exposures affect human health and disease. We focus on areas where zebrafish have been most effectively used in ecotoxicology and in environmental health, including investigation of exposures to endocrine disruptors, industrial waste byproducts, and arsenic.

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“…Some of these in vitro methods have the potential to screen thousands of compounds for their effects on complex pathways relevant to developmental processes and toxicities. 92 Many possible models have been explored, including hydra regeneration, 93 103 in vivo larval zebrafish assays, 104,105 and ESCs. 106,107 In some laboratories, murine ESCs were the model of choice for developmental toxicology studies.…”

Section: The Use Of Hpscs As Models For Developmental Toxicologymentioning

confidence: 99%

Human pluripotent stem cells as tools for high-throughput and high-content screening in drug discovery

Allison

Powles-Glover²,

Biga³

et al. 2015

IJHTS

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A significant bottleneck in drug discovery is the lack of suitable models for sensitive, reliable, and rapid assessment of lead molecules in preclinical stages of drug discovery. Human pluripotent stem cells (hPSCs) derived either from early human blastocysts (human embryonic stem cells) or by reprogramming somatic cells to a pluripotent state (human-induced pluripotent stem cells) can be propagated extensively in vitro while retaining the ability to differentiate into any specialized cell type within the body. In this review, we discuss how these unique features of hPSCs could offer a way of producing relevant in vitro models amenable to high-throughput testing for drug discovery. We summarize recent progress in inducing differentiation of hPSCs to specific cell types, and describe the ongoing efforts in applying hPSCs and their differentiated derivatives in disease modeling, drug discovery, and developmental toxicology. Moreover, we review the applications of high-content imaging assays in detecting the changes in the phenotype of hPSCs and their differentiated progeny. Finally, we highlight challenges that need to be overcome in order for the application of hPSC technology to fully benefit drug discovery.

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Inter-laboratory assessment of a harmonized zebrafish developmental toxicology assay – Progress report on phase I

Cited by 101 publications

References 21 publications

Behavioral screening of the LOPAC1280 library in zebrafish embryos

Behavioral screening of the LOPAC1280 library in zebrafish embryos

Zebrafish in Toxicology and Environmental Health

Human pluripotent stem cells as tools for high-throughput and high-content screening in drug discovery

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