Developmental Exposure of Mice to T-2 Toxin Increases Astrocytes and Hippocampal Neural Stem Cells Expressing Metallothionein.

Abstract

We previously reported that developmental exposure to T-2 toxin caused transient disruption of the hippocampal neurogenesis targeting neural stem cells (NSCs) and early-stage progenitor cells involving oxidative stress on weaning in mouse offspring. The present study examined metallothionein (MT) expression changes and their cellular identity in brain regions of these animals. T-2 toxin at 0, 1, 3, and 9mg/kg was given in the diet of maternal mice from gestational day 6 to postnatal day (PND) 21 on weaning. Offspring were maintained through PND 77 without T-2 toxin exposure. Male offspring were analyzed. Immunohistochemically, MT-I/II+ cells increased in the subgranular zone (SGZ) of the dentate gyrus and cerebral cortex at ≥ 3mg/kg and in the hilus of the dentate gyrus, corpus callosum, and cerebellum at 9mg/kg on PND 21, suggestive of operation of cytoprotective function against oxidative stress throughout the brain. Double immunohistochemistry analysis revealed MT-I/II+ SGZ cells to be NSCs and MT-I/II+ cells in other brain regions to be astrocytes as toxicity targets of T-2 toxin. Phosphorylated STAT3+ cell numbers increased only in the cerebellum in parallel with the increase of GFAP+ astrocytes at 9mg/kg, suggesting a STAT3-mediated transcriptional GFAP upregulation in cerebellar astrocytes. In the dentate gyrus, Il1a, Il1r1, and Mt2 increased transcripts at 9mg/kg, suggesting activation of the IL-1 signaling cascade, possibly causing MT-II upregulation. The increase of MT-I/II+ cells in all brain regions disappeared or was suppressed below the control level on PND 77, suggesting a recovery from the T-2 toxin-induced oxidative stress.