Gene expression profile of brain regions reflecting aberrations in nervous system development targeting the process of neurite extension of rat offspring exposed developmentally to glycidol

Abstract

We previously found that exposure to glycidol at 1000 ppm in drinking water caused axonopathy in maternal rats and aberrations in late-stage hippocampal neurogenesis, targeting the process of neurite extension in offspring. To identify the profile of developmental neurotoxicity of glycidol, pregnant Sprague-Dawley rats were given drinking water containing glycidol from gestational day 6 until weaning on day 21 after delivery, and offspring at 0, 300 and 1000 ppm were subjected to region-specific global gene expression profiling. Four brain regions were selected to represent both cerebral and cerebellar tissues, i.e., the cingulate cortex, corpus callosum, hippocampal dentate gyrus and cerebellar vermis. Downregulated genes in the dentate gyrus were related to axonogenesis (Nfasc), myelination (Mal, Mrf and Ugt8), and cell proliferation (Aurkb and Ndc80) at ≥ 300 ppm, and upregulated genes were related to neural development (Frzb and Fzd6) at 1000 ppm. Upregulation was observed for genes related to myelination (Kl, Igf2 and Igfbp2) in the corpus callosum and axonogenesis and neuritogenesis (Efnb3, Tnc and Cd44) in the cingulate cortex, whereas downregulation was observed for genes related to synaptic transmission (Thbs2 and Ccl2) in the cerebellar vermis; all of these changes were mostly observed at 1000 ppm. Altered gene expression of Cntn3, which functions on neurite outgrowth-promotion, was observed in all four brain regions at 1000 ppm. Gene expression profiles suggest that developmental exposure to glycidol affected plasticity of neuronal networks in the broad brain areas, and dentate gyrus neurogenesis may be the sensitive target of this type of toxicity.