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Neuro-toxicogenomic mapping of TMT induced neurotoxicity using human minibrain reveals associated adverse outcome events

View ORCID ProfileGovindan Subashika, View ORCID ProfileAlpern Daniel, View ORCID ProfileLuc Stoppini, View ORCID ProfileBart Deplancke, View ORCID ProfileRoux Adrien
doi: https://doi.org/10.1101/2022.01.21.477206
Govindan Subashika
1Tissue Engineering Laboratory, HEPIA HES-SO, University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland
2Arima Life Sciences Pvt Ltd, Chennai, India
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Alpern Daniel
3EPFL, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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Luc Stoppini
1Tissue Engineering Laboratory, HEPIA HES-SO, University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland
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Bart Deplancke
3EPFL, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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Roux Adrien
1Tissue Engineering Laboratory, HEPIA HES-SO, University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland
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  • For correspondence: adrien.roux@hesge.ch
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Abstract

Genome-wide transcriptomic interrogation of organoids and 3D tissue models are increasingly used for characterizing drug, toxicity responses and neurodevelopmental disorders. We established here a neuro-toxicogenomic assay by utilizing “minibrain”, a human in vitro 3D brain model system and a low-cost, highly multiplexable RNA-seq methodology (BRB-seq) for screening the effect of trimethyltin chloride (TMT) induced neurotoxicity. We demonstrate that transcriptomic profiling is insightful to the cellular composition and regional identity of the minibrain. Further, we characterize the transcriptomic changes associated with the dose-time neurotoxic response of minibrain upon exposure to TMT. The distinct gene expression changes and molecular candidates identified with our pipeline provides insight to map the key events involved in the adverse outcome pathway of TMT associated neurotoxicity. We identify processes such as endoplasmic reticulum stress, dysregulation of synaptic genes and downregulation of neuron-morphology associated genes upon exposure to TMT. In response to TMT, we identify activation of an early response homeostatic mechanism in minibrain and an interplay of STAT pathways correlating with the dose severity. In this study, we present a neuro-toxicogenomic assay that demonstrates the power of a low-cost transcriptomic screening to study chemical induced neurotoxicity.

Competing Interest Statement

Dr. Daniel Alpern and Prof.Bart Deplancke are shareholders of Alithea Genomics SA. Dr. Subashika Govindan was employed by HEPIA and was employed ARMIA Lifesciences PVT Ltd during the project.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 23, 2022.
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Neuro-toxicogenomic mapping of TMT induced neurotoxicity using human minibrain reveals associated adverse outcome events
Govindan Subashika, Alpern Daniel, Luc Stoppini, Bart Deplancke, Roux Adrien
bioRxiv 2022.01.21.477206; doi: https://doi.org/10.1101/2022.01.21.477206
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Neuro-toxicogenomic mapping of TMT induced neurotoxicity using human minibrain reveals associated adverse outcome events
Govindan Subashika, Alpern Daniel, Luc Stoppini, Bart Deplancke, Roux Adrien
bioRxiv 2022.01.21.477206; doi: https://doi.org/10.1101/2022.01.21.477206

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