Glycidol Induces Axonopathy by Adult-Stage Exposure and Aberration of Hippocampal Neurogenesis Affecting Late-Stage Differentiation by Developmental Exposure in Rats

Abstract

To investigate the neurotoxicity profile of glycidol and its effect on developmental hippocampal neurogenesis, pregnant Sprague Dawley rats were given drinking water containing 0, 100, 300, or 1000 ppm glycidol from gestational day 6 until weaning on day 21 after delivery. At 1000 ppm, dams showed progressively worsening gait abnormalities, and histopathological examination showed generation of neurofilament-L(+) spheroids in the cerebellar granule layer and dorsal funiculus of the medulla oblongata, central chromatolysis in the trigeminal nerve ganglion cells, and axonal degeneration in the sciatic nerves. Decreased dihydropyrimidinase-like 3(+) immature granule cells in the subgranular zone (SGZ) and increased immature reelin(+) or calbindin-2(+) γ-aminobutyric acid-ergic interneurons and neuron-specific nuclear protein (NeuN)(+) mature neurons were found in the dentate hilus of the offspring of the 1000 ppm group on weaning. Hilar changes remained until postnatal day 77, with the increases in reelin(+) and NeuN(+) cells being present at ≥ 300 ppm, although the SGZ change disappeared. Thus, glycidol caused axon injury in the central and peripheral nervous systems of adult rats, suggesting that glycidol targets the newly generating nerve terminals of immature granule cells, resulting in the suppression of late-stage hippocampal neurogenesis. The sustained hilar changes may be a sign of continued aberrations in neurogenesis and migration. The no-observed-adverse-effect level was determined to be 300 ppm (48.8mg/kg body weight/day) for dams and 100 ppm (18.5mg/kg body weight/day) for offspring. The sustained developmental exposure effect on offspring neurogenesis was more sensitive than the adult axonal injury.

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

“…may be caused by feedback control for anti-apoptosis in response to the reduction in the number of immature granule cells. Although we previously did not detect changes in cellular kinetics on cell proliferation and apoptosis by immunohistochemistry and the TUNEL-assay (Akane et al, 2013a), we could show the possibility of glycidol-induced suppression of cell proliferation and apoptosis in the dentate gyrus by microarray analysis. In the corpus callosum, which was selected to represent white matter tissues, we observed transcript upregulation of genes related to growth, survival and function of glial cells, i.e.…”

“…Therefore, it may be reasonable to investigate developmental neurotoxicity in the hippocampal dentate gyrus using microarray techniques. We have recently revealed that dams of the present study exposed to glycidol at 1000 ppm induced axonal injury involving both central and peripheral nervous systems (Akane et al, 2013a). In the central nervous system, axonal injury was apparent in the cerebellum and medulla oblongata.…”

“…Therefore, toxicants targeting axon terminals and synaptosomes, as well as cell proliferation, may cause developmental neurotoxicity, as we have previously shown with acrylamide (Ogawa et al, 2011(Ogawa et al, , 2012. We have recently found that oral exposure to glycidol at 1000 ppm in drinking water induced progressive gait abnormalities and axonopathy involving both central and peripheral nervous systems in maternal rats (Akane et al, 2013a). Offspring of these dams exhibited a decreased number of TUC-4 + cells, which are considered to be immature granule cells (Knoth et al, 2010) that have dendritic growth cones and recurrent basal dendrites (Ribak et al, 2004) in the SGZ of the hippocampal dentate gyrus (Akane et al, 2013a).…”

“…The present experiments were identical to that previously reported (Akane et al, 2013a). In brief, pregnant rats were randomly divided into four groups of 12 animals and were treated with 0, 100, 300 or 1000 ppm glycidol in drinking water from GD 6 to PND 21.…”

“…We have recently found that oral exposure to glycidol at 1000 ppm in drinking water induced progressive gait abnormalities and axonopathy involving both central and peripheral nervous systems in maternal rats (Akane et al, 2013a). Offspring of these dams exhibited a decreased number of TUC-4 + cells, which are considered to be immature granule cells (Knoth et al, 2010) that have dendritic growth cones and recurrent basal dendrites (Ribak et al, 2004) in the SGZ of the hippocampal dentate gyrus (Akane et al, 2013a). These results suggest that glycidol affects both axon terminals and neurogenesis by a common mechanism targeting the axon terminals in adult animals and newly generating nerve terminals of immature granule cells.…”