Neurotoxins Induced Toxicogenomic Patterns on Human Induced Pluripotent Stem Cell based Microphysiological System

Abstract

The traditional testing requirements for both adult and developmental neurotoxicity evaluations are based on in vivo animal models while the neurotoxic risks associated with molecules or vaccines is mainly determined by neurobehavioral and neuropathological effects in the experimental model chosen. The poor correlation between preclinical in vitro or in vivo data (non-human) with the real time clinical effects leading to severe progressive adverse events is a major concern in general. The employed bioinformatics search tools helped us to short list the affected common genes in neurotoxicity induced by viral, bacterial infections and cytokine storms. Here, we used our group characterized human induced Pluripotent Stem Cell (hiPSC) system developed as an in vitro microphysiological model to record phenotype and genotype perturbations when treated with selected known representative neurotoxins like TEA, Tetanus toxin, MSG, Dopamine, Bungarotoxin etc. The objective was to assess the application qualification of the novel in vitro model that yields human relevant readouts. The recorded phenotype perturbations were barcoded with SOD, BAX, HDAC1, TNFalpha, MAPK14 like gene expressions in generating in vitro patterns to correlate the human functional toxicogenomics information. We showed hiPSC system to be phenotypically responsive and genotypically reactive when treated with neurotoxins. Out of 7 gene expression data sets generated, SOD and BAX were recorded to be downregulated at all the micro-conditions created in the hiPSC system while HDAC was consistently upregulated except in Dopamine treated system. The bioinformatics analysis performed on the selected genes gave insight into their roles in disease specific signalling pathways like JAK-STAT, TNF, Neurotrophin etc. We report configured hiPSC system suitability as an in vitro human surrogate platform/model in generating toxicogenomics signatures to support prediction on the test material in any assay system developed on this well characterized microphysiological base.