Redox-regulated transcriptomics of contrasting cellular differentiation states. Mus musculus

Valproic acid (VPA) is a common anti-epileptic drug and known neurodevelopmental toxicant. The exact mechanism of VPA toxicity remains unknown, however research shows that VPA induces redox dysregulation and inhibits neurogenesis in undifferentiated cells but has little effect in fully differentiated neurons. We hypothesize that VPA causes redox-sensitive post-translational and transcriptional alterations that are dependent upon cellular differentiation states. Undifferentiated murine P19 cells and P19-derived neurons were treated with VPA alone or pretreated with D3T, an inducer of the NRF2 antioxidant pathway, prior to VPA exposure. Treatment with VPA increased oxidative post-translational protein modifications in undifferentiated cells but had no effect in fully differentiated neurons. Pretreatment with D3T decreased post-translational and transcriptional dysregulation in VPA-treated undifferentiated cells. Our findings demonstrate the effectiveness of NRF2-mediated protection in maintaining redox homeostasis during early neurogenesis.