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Late Effect of Developmental Exposure to 3,3′-Iminodipropionitrile on Neurogenesis in the Hippocampal Dentate Gyrus of Mice

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Abstract

The effects of developmental exposure to 3,3′-iminodipropionitrile (IDPN), a neurotoxicant that causes proximal axonopathy, on mouse hippocampal neurogenesis was examined. Pregnant mice were exposed to IDPN at 0, 600, or 1200 ppm in their drinking water from gestational day 6 to postnatal day (PND) 21. On PND 21, male offspring showed increased postmitotic neuron-specific NeuN-immunoreactive(+) granule cell numbers in the dentate subgranular zone (SGZ) and granule cell layer (GCL) and decreased glutamate receptor gene Grin2d levels in the dentate gyrus at 1200 ppm. On PND 77, decreased numbers were observed for TBR2+ progenitor cells in the SGZ at ≥600 ppm and GFAP+ stem cells, DCX+ progenitor cells and immature granule cells, NeuN+ immature and mature granule cells, PCNA+ proliferating cells in the SGZ and/or GCL, and immunoreactive cells for ARC or FOS, immediate-early gene products related to neuronal and synaptic plasticity, in the GCL at 1200 ppm. Additionally, at 1200 ppm of IDPN, downregulation of Kit, the gene encoding the stem cell factor (SCF) receptor, and upregulation of Kitl, encoding SCF, were observed in the dentate gyrus. Therefore, maternal IDPN exposure in mice affects neurogenesis involving glutamatergic signals at the end of developmental exposure, with late effects suppressing SGZ cell proliferation, reducing the broad range of granule cell lineage population, which may be responsible for SCF receptor downregulation. The upregulated SCF was likely a feedback response to the decreased receptor level. These results suggest that reduced SCF signaling may cause suppressed neuronal and synaptic plasticity.

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Abbreviations

ARC:

Activity-regulated cytoskeleton-associated protein

BDNF:

Brain-derived neurotrophic factor

BLBP:

Brain lipid-binding protein

CALB1:

Calbindin-D-28K

CALB2:

Calbindin-D-29K

C T :

Threshold cycle

DCX:

Doublecortin

FOS:

FBJ osteosarcoma oncogene

GABA:

γ-Aminobutyric acid

GCL:

Granule cell layer

GD:

Gestational day

GFAP:

Glial fibrillary acidic protein

GRIN2D:

Glutamate receptor, ionotropic, NMDA2D (epsilon 4)

IDPN:

3,3′-Iminodipropionitrile

IEG:

Immediate-early gene

mRNA:

Messenger RNA

NeuN:

Neuron-specific nuclear protein

NMDA:

N-methyl-D-aspartate

NR2D:

Glutamate receptor, ionotropic, NMDA2D (epsilon 4)

PCNA:

Proliferating cell nuclear antigen

PFA:

Paraformaldehyde

Phospho-NF-H:

Phosphorylated neurofilament, heavy polypeptide

PND:

Postnatal day

PVALB:

Parvalbumin

RELN:

Reelin

RT-PCR:

Reverse-transcription polymerase chain reaction

SCF:

Stem cell factor

SGZ:

Subgranular zone

TBR2:

T-box brain 2

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick-end labeling

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Acknowledgements

The authors thank Mrs. Shigeko Suzuki for her technical assistance in preparing the histological specimens. This work was supported by a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (JSPS; grant no. 25292170).

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Correspondence to Makoto Shibutani.

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All authors declare no actual or potential conflicts 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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Hasegawa-Baba, Y., Tanaka, T., Watanabe, Y. et al. Late Effect of Developmental Exposure to 3,3′-Iminodipropionitrile on Neurogenesis in the Hippocampal Dentate Gyrus of Mice. Neurotox Res 32, 27–40 (2017). https://doi.org/10.1007/s12640-017-9703-3

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  • DOI: https://doi.org/10.1007/s12640-017-9703-3

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