Differentiated and mature neurons are more responsive to neurotoxicant exposure at both transcriptional and translational levels.

SH-SY5Y human neuroblastoma cells have been extensively used as an in vitro model system in a diverse range of studies involving neurodevelopment, neurotoxicity, neurodegeneration, and neuronal ageing. Both naïve and differentiated phenotypes of SH-SY5Y cells are utilized to model human neurons under in vitro conditions. The process of differentiation causes extensive remodeling of neuronal cells at multiple omic levels, including the epigenome and proteome. In the present investigation, the miRNAome and proteome profiles of arsenic-treated naïve and differentiated SH-SY5Y cells were generated using the miRNA OpenArray technology and high-resolution mass spectrometry. Our findings demonstrated that differentiation dramatically affected the response of SH-SY5Y cells to toxicant exposure, as indicated by increased tolerance of differentiated cells against arsenic exposure compared to naïve cells in cell viability assay. Arsenic-exposed naïve and differentiated SH-SY5Y cells possess distinct miRNA and protein profiles with few similarities. Compared to naïve cells, differentiated cells have undergone higher deregulation in the expression of brain-enriched miRNAs and proteins and have shown a more drastic decrease in oxygen consumption rate, which is a measure of mitochondrial respiration after exposure to arsenic. Proteins identified in arsenic-treated differentiated SH-SY5Y cells were more enriched in pathways underlying multifactorial neurotoxic events. Additionally, more functional regulatory modules have been identified between the miRNAs and proteins differentially expressed in arsenic-treated differentiated SH-SY5Y cells relative to naïve cells. Collectively, our studies have shown that differentiated SH-SY5Y cells displayed alterations in the expression of a greater number of miRNAs and proteins following neurotoxicant exposure, indicating their higher responsivity.