Effects of developmental toxicants on microRNA expression during neural differentiation of murine embryonic stem cells

Studying chemical disturbances during neural differentiation ofmurine embryonic stem cells (mESC) has been established atZEBET as an alternative in vitro testing approach for the identificationand classification of developmental toxicants. Manystudies have shown an essential role of microRNAs in posttranscriptionalregulation of gene expression during developmentand ESC differentiation. Thus, neural differentiation of ESC invitro allows investigation of the role of miRNAs in chemicalmediateddevelopmental toxicity. The main goal of this projectwas to analyze the expression of neural-specific miRNAs duringneural differentiation of mESC while being exposed to thedevelopmental neurotoxicants. The substances we mainly focusedon comprise valproic acid (VPA), arsenic and curcumin.All these substances have been shown in vitro and/or in vivo toexert effects on miRNA expression and to affect neural development.The developmental neurotoxicity of these substances aswell as their effects on miRNA expression during neural differentiationof mESC will be discussed. We could demonstrate thatneural-specific or enriched miRNAs show different expressionpatterns during neural differentiation of mESC when cells arebeing exposed to VPA. So, the expression of mir-128a and mir-124a decreased with increasing VPA concentrations, whereaslet-7c was 2-fold upregulated. The downregulation of mir-128aand mir-124a in cells treated with VPA was stronger comparedto the concurrent downregulation of the neuron-specific markerƒÀIII-tubulin. The effects of VPA on neuron-specific mir-124aexpression may point to possible compound-mediated mechanismsexerted through mir-124a-dependent regulation pathways.