ZeTox – Toxicology Services

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icon-zeglobaltox ZeGlobalTox – 3 Analysis Into a 1 Procedure

ZeGlobalTox is a novel experimental procedure that integrates the analysis of cardio-, neuro-, and hepatotoxicity into a single procedure. The three sequential assays are performed in the same larvae, allowing the reduction of zebrafish used compared to parallel assessments, and streamlining the experimental pipeline. In addition, the high predictivity of ZeGlobalTox allows reducing the use of mammals for organ-toxicity screening in later research stages.

ZeGlobalTox Service

Integrative methodology for in vivo organ-toxicity screening.

Advantages

Simultaneous assessment of NeuroTox, CardioTox and HepatoTox.

High predictivity referred to humans: 89% specificity, 68% sensitivity and 78% accuracy.

Animal testing and drug volumes reducement.

Method description

A zebrafish transgenic line expressing green fluorescent protein (GFP) in cardiomyocytes and red fluorescent protein (RFP) in hepatocytes is used to determine cardiotoxicity, neurotoxicity, and hepatotoxicity. We offer a basic and an extended protocol to evaluate neurotoxicity or CNS side effects upon long (24h) and acute (3h) exposure to potentially toxic compounds, respectively.

Figure 1. Comparison of toxic exposure times and toxicity evaluation timepoints of basic and extended protocols.

Readouts

  • Neurotoxicity
    • Changes in the basal locomotor activity
    • Altered response to light stimuli
    • Thigmotaxis (extended protocol)
    • Habituation (extended protocol)
    • Seizures (extended protocol)
  • Cardiotoxicity
    • Heartbeat frequency (ventricle and atrium)
    • Arrhythmias
    • Ejection fraction
    • QT prolongation
    • Heart chamber (Atrium/Ventricle) diameter
    • Cardiac arrest
  • Hepatotoxicity
    • Liver area: liver necrosis and hepatomegaly
    • Hepatic steatosis: fat accumulation in the liver
    • Liver function: yolk lipid retention
Figure 2. Larval videotracking of basal locomotion activity acquired by NOLDUS system. Red lines show larval movements.
ZeTox_Neurotox_Figure3_-Locomotion
Figure 3.  General motor activity assessment. Light/Dark locomotion pattern of zebrafish larvae in response to a negative control, to a neurotoxic compound (positive control) and a study compound that doesn’t produce neurotoxic effect on basal locomotor activity.
Figure 4. Heart tomography of 3dfp transgenic zebrafish larva labelling cardiomyocytes with GFP.
Figure 5. Yolk lipid retention evaluation. (A) Proportion of zebrafish larvae that show yolk lipid retention after treatment with a molecule of interest compared to negative and positive controls. (B) Representative images of zebrafish after specific fat staining showing a healthy larva (image on the right), larva with high amount of yolk lipid retention (middle) and larva with few amount of lipid retention (left).

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References

  1. Cornet C, Calzolari S, Miñana-Prieto R, Dyballa S, van Doornmalen E, Rutjes H, Savy T, D'Amico D, Terriente J. ZeGlobalTox: An Innovative Approach to Address Organ Drug Toxicity Using Zebrafish. Int J Mol Sci. 2017 Apr 19;18(4):864.