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.

Risks for human health related to the presence of 3‐ and 2‐monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food

“…In a 28‐day study neurotoxicity developed in 5‐week‐old Sprague‐Dawley rats which were given glycidol by gavage at 0, 30 or 200 mg/kg bw per day (Akane et al., ). Neurotoxicity was only observed at highest dose in which rats showed progressively increasing abnormalities of the gait along with essentially the same lesions of central and peripheral nervous systems as those also observed in pregnant rats (Akane et al., ).…”

Prognostic significance of contactin 3 expression and associated genes in glioblastoma multiforme

“…CNTN3 belongs to the Ig superfamily of proteins and its function is primarily associated with the properties of this family. Akane et al (23), illustrated that the rat ortholog of CNTN3, Cntn3 , functions in neurite outgrowth-promotion, and when treated with glycidol at 1,000 ppm, axonopathy occurred and the expression of CNTN3 was altered. Morales et al (10), found an isolated cryptic proximal interstitial 3p deletion, del(3) (p12.3p13) in a patient with neurodevelopmental delay.…”

Classification of advanced methods for evaluating neurotoxicity

“…Neural circuits can be assessed by measuring neurite growth, synaptogenesis, and myelination (Brat and Brimijoin 1992). Glycidol exposure increases the gene expression of Kl, Igf2, and Igfbp2 in the corpus callosum to promote myelination, while Efnb3, Tnc, and Cd44 gene expression increases in the cingulate cortex promote neurite growth (Akane et al 2014). The safety of galactose (Powell et al 1986) and methylmercury (Parran et al 2003) has been assessed by measuring neurite growth.…”