Developmental Exposure of Mice to T-2 Toxin Increases Astrocytes and Hippocampal Neural Stem Cells Expressing Metallothionein
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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 9 mg/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 ≥ 3 mg/kg and in the hilus of the dentate gyrus, corpus callosum, and cerebellum at 9 mg/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 9 mg/kg, suggesting a STAT3-mediated transcriptional GFAP upregulation in cerebellar astrocytes. In the dentate gyrus, Il1a, Il1r1, and Mt2 increased transcripts at 9 mg/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.
KeywordsT-2 toxin Metallothionein Developmental neurotoxicity Oxidative stress Mouse
The authors thank Shigeko Suzuki for her technical assistance in preparing the histological specimens and Yosuke Watanabe for his technical advice in this study.
This work was supported by Health and Labour Sciences Research Grants (Research on Food Safety) from the Ministry of Health, Labour and Welfare of Japan (Grant No. H28-shokuhin-ippan-004) and by a Research Fund from Institute of Global Innovation Research, Tokyo University of Agriculture and Technology.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Research Involving Human Participants and/or Animals
All procedures in this study were conducted in accordance with the Guidelines for Proper Conduct of Animal Experiments (Science Council of Japan, 1 June 2006) and according to the protocol approved by the Animal Care and Use Committee of The Tokyo University of Agriculture and Technology. All efforts were made to minimize animal suffering.
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