Dozens of compounds with unknown toxicity profiles in your hands: why entrust the screening to zebrafish?

From challenge to knowledge: the outstanding performance of zebrafish in predicting toxicity.

By Sergio Jarque, Head of Tox Services at ZeClinics.

Sergio Jarque is a researcher with more than 15 years of experience in (Eco-)Toxicology. During his career, he contributed to the development of innovative solutions for the detection of chemicals and their effects through cell-based and fish-based methods. In 2018 he joined ZeClinics, being responsible for the Toxicology Area since 2019.

 

Imagine a transparent window to observe the world through. A window that translates complex meanings and behaviors into understandable knowledge. A window that brings specific answers to specific questions. Would it be wonderful? Yes, we agree, incredibly challenging for such a window’s creator, but still amazing as a concept.

That is precisely the challenge we proposed, here at Zeclinics, to transparent zebrafish. Becoming a three millimeters window of knowledge, a tool able to turn unreadable signals into neat information.  Of course, a task widely recognized as enormous when applied to others is not expected to be easy for a little cyprinid. But, how is zebrafish doing so far? To be honest, really well. 

ZeClinics have known zebrafish. All this time served to delve into how zebrafish behave, how zebrafish lives and dies, what zebrafish find disturbing… And more importantly, we learned how all this knowledge could be used to understand more about humans. Because, and this is a fact, what disturbs zebrafish is very similar to what disturbs humans.

A little bit more scientific. In our hands, zebrafish can:

  • Predict teratogenicity related to humans with concordances above 80% (Jarque et al., 2020).
  • Achieve a more reliable prediction of cardiotoxicity than cellular systems and similar predictive performances to those obtained in dogs (Dyballa et al., 2019). 
  • Replicate phenotypes associated with neurotoxicants.
  • Identify compounds affecting the liver or the inner ear.
  • Detect chemicals with endocrine-disrupting activities, being one of the methods accepted for the regulatory bodies to identify endocrine disruptors (Jarque et al., 2019). 

Altogether, quite impressive for just a fish.

But the challenge is not complete yet, because we are sure that zebrafish can still perform better, not only in terms of prediction when screening large batteries of compounds but also for understanding the molecular basis behind the toxic response. The latter is a priority for us, and we are consequently orienting massive efforts in that direction. Undoubtedly, a complicated task is due to the inherent complexity of most biological processes. Still, the eagerness starts to pay off: now we can successfully identify teratogens and ascribe the potential mechanisms of action involved. We are sure that we will push the model further and unequivocally assign molecular pathways to specific molecules or groups of molecules soon. This may allow us to walk the path in the opposite direction, from chemical structure to molecular targets.

And this will not be just restricted to developmental toxicity. Identifying molecular targets and establishing well-defined adverse outcome pathways are anticipated as key elements for understanding the events involved in toxicity, regardless of the biological context. Therefore, it is expected that all services are included in our Zetox Platform, namely:

and some others to come will benefit from this approach. Our minds' final goal is to match zebrafish effective concentrations to those reported in humans for different biological endpoints.

Yes, we know it may sound too ambitious, but zebrafish and ZeClinics accepted the challenge some years ago, and we are not going to abandon it now that things are getting more and more interesting.

Our model:

  • Is informative and predictive.
  • Shortens experimental times while increases statistical significance.
  • Includes metabolic reactions and bioavailability studies. 
  • It is adaptable to automated imaging platforms, which contributes to objectify the observations.
  • Benefits from genome editing methods to obtain transgenic lines in a relatively easy manner.

These skills make zebrafish an ideal player for the screening of large amounts of compounds and potential leads' characterization. Soon, all this will be complemented with deeper knowledge on molecular pathways and additional comparative studies that will bring prediction to upper levels. For us, an exciting journey to run; for our clients, a valuable source of information.

 

REFERENCES:

[1] S. Jarque, M. Rubio-Brotons, J. Ibarra, V. Ordoñez, S. Dyballa, R. Miñana, J. Terriente, Morphometric analysis of developing zebrafish embryos allows predicting teratogenicity modes of action in higher vertebrates, Reprod. Toxicol. 96 (2020) 337–348. https://doi.org/10.1016/j.reprotox.2020.08.004.

[2] S. Dyballa, R. Miñana, M. Rubio-Brotons, C. Cornet, T. Pederzani, G. Escaramis, R. Garcia-Serna, J. Mestres, J. Terriente, Comparison of Zebrafish Larvae and hiPSC Cardiomyocytes for Predicting Drug-Induced Cardiotoxicity in Humans, Toxicol. Sci. 171 (2019) 283–295. https://doi.org/10.1093/toxsci/kfz165.

[3] S. Jarque, J. Ibarra, M. Rubio-Brotons, J. García-Fernández, J. Terriente, Multiplex analysis platform for endocrine disruption prediction using zebrafish, Int. J. Mol. Sci. 20 (2019). https://doi.org/10.3390/ijms20071739.

 

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