Glycidol induces axonopathy and aberrations of hippocampal neurogenesis affecting late-stage differentiation by exposure to rats in a framework of 28-day toxicity study

Abstract

Developmental exposure to glycidol induces aberrations of late-stage neurogenesis in the hippocampal dentate gyrus of rat offspring, whereas maternal animals develop axonopathy. To investigate the possibility whether similar effects on adult neurogenesis could be induced by exposure in a framework of 28-day toxicity study, glycidol was orally administered to 5-week-old male Sprague-Dawley rats by gavage at 0, 30 or 200 mg/kg for 28 days. At 200 mg/kg, animals revealed progressively worsening gait abnormalities as well as histopathological and immunohistochemical changes suggestive of axonal injury as evidenced by 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. At the same dose, animals revealed aberrations in neurogenesis at late-stage differentiation as evidenced by decreases of both doublecortin(+) and dihydropyrimidinase-like 3(+) cells in the subgranular zone (SGZ) and increased reelin(+) or calbindin-2(+) γ-aminobutyric acid-ergic interneurons and neuron-specific nuclear protein(+) mature neurons in the dentate hilus. These effects were essentially similar to that observed in offspring after maternal exposure to glycidol. These results suggest that glycidol causes aberrations in adult neurogenesis in the SGZ at the late stage involving the process of neurite extension similar to the developmental exposure study in a standard 28-day toxicity study.

Keywords: 3,3′-diaminobenzidine; Axonopathy; C(T); Calb1; Calb2; Calbindin-D-28K; Calretinin; DAB; DCX; Dihydropyrimidinase-like 3; Doublecortin; Dpysl3; GABA; GFAP; Gamma-aminobutyric acid; Gapdh; Glial fibrillary acidic protein; Glyceraldehyde 3-phosphate dehydrogenase; Glycidol; Hippocampal dentate gyrus; Hprt; Hypoxanthine phosphoribosyltransferase 1; MMI; Methimazole; NF-L; NeuN; Neurofilament-L; Neurogenesis; Neuron-specific nuclear protein; Neurotoxicity; PBS; PCNA; Paired box 6; Parvalbumin; Pax6; Phosphate-buffered saline; Phosphorylated neurofilament-H; Proliferating cell nuclear antigen; Pvalb; RT-PCR; Reverse-transcription polymerase chain reaction; SGZ; Subgranular zone; T box brain 2; T(3); T(4); TSH; TUNEL; Tbr2; Terminal deoxynucleotidyl transferase dUTP nick end labeling; Threshold cycle; Thyroid-stimulating hormone; Thyroxine; Triiodothyronine; p-NF-H.