Abstract
To determine the developmental exposure effects of T-2 toxin on postnatal hippocampal neurogenesis, pregnant ICR mice were provided a diet containing T-2 toxin at 0, 1, 3, or 9 ppm from gestation day 6 to day 21 on weaning after delivery. Offspring were maintained through postnatal day (PND) 77 without T-2 toxin exposure. In the hippocampal dentate gyrus of male PND 21 offspring, GFAP+ and BLBP+ type-1 stem cells and PAX6+ and TBR2+ type-2 progenitor cells decreased in the subgranular zone (SGZ) at 9 and ≥3 ppm, respectively, in parallel with increased apoptosis at ≥3 ppm. In the dentate hilus, reelin+ γ-aminobutyric acid (GABA)-ergic interneurons increased at 9 ppm, suggesting reflection of neuronal mismigration. T-2 toxin decreased transcript levels of cholinergic and glutamate receptor subunits (Chrna4, Chrnb2 and Gria2) and glutamate transporter (Slc17a6) in the dentate gyrus, suggesting decreased cholinergic signals on hilar GABAergic interneurons innervating type-2 cells and decreased glutamatergic signals on type-1 and type-2 cells. T-2 toxin decreased SGZ cells expressing stem cell factor (SCF) and increased cells accumulating malondialdehydes. Neurogenesis-related changes disappeared on PND 77, suggesting that T-2 toxin reversibly affects neurogenesis by inducing apoptosis of type-1 and type-2 cells with different threshold levels. Decreased cholinergic and glutamatergic signals may decrease type-2 cells at ≥3 ppm. Additionally, decreased SCF/c-Kit interactions and increased oxidative stress may decrease type-1 and type-2 cells at 9 ppm. The no-observed-adverse-effect level for offspring neurogenesis was determined to be 1 ppm (0.14–0.49 mg/kg body weight/day).
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The authors thank Mrs. Shigeko Suzuki for her technical assistance in preparing the histological specimens.
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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. H25-shokuhin-ippan-009).
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Tanaka, T., Abe, H., Kimura, M. et al. Developmental exposure to T-2 toxin reversibly affects postnatal hippocampal neurogenesis and reduces neural stem cells and progenitor cells in mice. Arch Toxicol 90, 2009–2024 (2016). https://doi.org/10.1007/s00204-015-1588-4
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DOI: https://doi.org/10.1007/s00204-015-1588-4