RT Journal Article
SR Electronic
T1 Neuro-toxicogenomic mapping of TMT induced neurotoxicity using human minibrain reveals associated adverse outcome events
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.21.477206
DO 10.1101/2022.01.21.477206
A1 Govindan Subashika
A1 Alpern Daniel
A1 Luc Stoppini
A1 Bart Deplancke
A1 Roux Adrien
YR 2022
UL http://biorxiv.org/content/early/2022/01/23/2022.01.21.477206.abstract
AB 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 StatementDr. 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.