Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres

Abstract

Stress in early life has been linked with the development of late-life neurological disorders. Early developmental age is potentially sensitive to several environmental chemicals such as alcohol, drugs, food contaminants, or air pollutants. The recent advances using three-dimensional neural sphere cultures derived from pluripotent stem cells have provided insights into the etiology of neurological diseases and new therapeutic strategies for assessing chemical safety. In this study, we investigated the neurodevelopmental effects of exposure to thalidomide (TMD); 2,2′,4,4′-tetrabromodiphenyl ether; bisphenol A; and 4-hydroxy-2,2′,3,4′,5,5′,6-heptachlorobiphenyl using a human embryonic stem cell (hESC)-derived sphere model. We exposed each chemical to the spheres and conducted a combinational analysis of global gene expression profiling using microarray at the early stage and morphological examination of neural differentiation at the later stage to understand the molecular events underlying the development of hESC-derived spheres. Among the four chemicals, TMD exposure especially influenced the differentiation of spheres into neuronal cells. Transcriptomic analysis and functional annotation identified specific genes that are TMD-induced and associated with ERK and synaptic signaling pathways. Computational network analysis predicted that TMD induced the expression of DNA-binding protein inhibitor ID2, which plays an important role in neuronal development. These findings provide direct evidence that early transcriptomic changes during differentiation of hESCs upon exposure to TMD influence neuronal development in the later stages.

Inhibition of Ganglioside Synthesis Suppressed Liver Cancer Cell Proliferation through Targeting Kinetochore Metaphase Signaling

“…In accordance with this, the Bayesian network showed that the node of TP53 was located at the top of the network hierarchy, and the strongest connection was observed between TP53 and AURKB ( Figure 5 B). The Bayesian network represents the joint posterior probability distribution over the whole set of variables in a system and is considered more biologically interpretable because of the removal of indirect correlations [ 36 ]. Intriguingly, upstream regulator analysis, the causal analytics algorithms in IPA, revealed that TP53 was the only upstream transcription regulator of AURKB, whose expression was regulated by PDMP in JHH7 cells ( Figure S6 ).…”

Establishment of a novel non-integrated human pluripotent stem cell-based gastruloid model

“…Extensive toxicological evaluations reveal that the use of THD by expectant mothers is associated with severe congenital malformations in offspring, such as thumb loss, limb dysplasia, neurodevelopmental retardation, and congenital heart disease 31 . Several stem cell-based models have previously been utilized to investigate the effects of THD 37,[49][50][51] ; However, most of these models lack the crucial spatiotemporal and morphological context of the developing embryo. Furthermore, the precise effects of THD on early embryonic development of human remains unclear.…”

Integrative Approaches of Bioassay and Computational Analysis for Discovering Potential Bioactive Compounds and Predictive Toxicity

“…To perform a computational toxicity assessment using the chemical structure of the components contained in foods is the same as ascertaining a quantitative structure-activity relationship (QSAR) using the information of the chemical structural formula as a parameter. Evaluation by computational toxicology is energetically underway for environmentally hazardous substances and drug candidate substances (1).…”