Abstract
Lead (Pb) causes developmental neurotoxicity. Developmental exposure to Pb acetate (PbAc) induces aberrant hippocampal neurogenesis by increasing or decreasing neural progenitor cell (NPC) subpopulations in the dentate gyrus (DG) of rats. To investigate whether hippocampal neurogenesis is similarly affected by PbAc exposure in a general toxicity study, 5-week-old Sprague–Dawley rats were orally administered PbAc at 0, 4000, and 8000 ppm (w/v) in drinking water for 28 days. After exposure to 4000 or 8000 ppm PbAc, Pb had accumulated in the brains. Neurogenesis was suppressed by 8000 ppm PbAc, which was related to decreased number of type-2b NPCs, although number of mature granule cells were increased by both PbAc doses. Gene expression in the 8000 ppm PbAc group suggested suppressed NPC proliferation and increased apoptosis resulting in suppressed neurogenesis. PbAc exposure increased numbers of metallothionein-I/II+ cells and GFAP+ astrocytes in the DG hilus, and upregulated Mt1, antioxidant genes (Hmox1 and Gsta5), and Il6 in the DG, suggesting the induction of oxidative stress and neuroinflammation related to Pb accumulation resulting in suppressed neurogenesis. PbAc at 8000 ppm also upregulated Ntrk2 and increased the number of CALB2+ interneurons, suggesting the activation of BDNF-TrkB signaling and CALB2+ interneuron-mediated signals to ameliorate suppressed neurogenesis resulting in increased number of newborn granule cells. PbAc at both doses increased the number of ARC+ granule cells, suggesting the facilitation of synaptic plasticity of newborn granule cells through the activation of BDNF-TrkB signaling. These results suggest that PbAc exposure during the young-adult stage disrupted hippocampal neurogenesis, which had a different pattern from developmental exposure to PbAc. However, the induction of oxidative stress/neuroinflammation and activation of identical cellular signals occurred irrespective of the life stage at PbAc exposure.
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Acknowledgements
The authors thank Yayoi Kohno for her technical assistance in preparing the histological specimens. We also thank J. Ludovic Croxford, Ph.D., from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
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This work was supported by Health and Labour Sciences Research Grants (Research on Risk of Chemical Substances) from the Ministry of Health, Labour and Welfare of Japan (Grant No. 19KD1003); Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (JSPS; Grant No. 18H02341); and a Research Fund from Institute of Global Innovation Research, Tokyo University of Agriculture and Technology.
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Natsuno Maeda: methodology, formal analysis, investigation, data curation, writing—original draft, visualization. Saori Shimizu: methodology, formal analysis, investigation, data curation, writing—review and editing. Yasunori Takahashi: investigation, data curation, writing—review and editing. Reiji Kubota: investigation, data curation, writing—review and editing. Suzuka Uomoto: investigation, writing—review and editing. Keisuke Takesue: investigation, writing—review and editing. Kazumi Takashima: investigation, writing—review and editing. Hiromu Okano: investigation, writing—review and editing. Ryota Ojiro: investigation, writing—review and editing. Shunsuke Ozawa: investigation, writing—review and editing. Qian Tang: investigation, writing—review and editing. Meilan Jin: methodology, data curation, writing—review and editing. Yoshiaki Ikarashi: validation, writing—review and editing. Toshinori Yoshida: investigation, writing—review and editing. Makoto Shibutani: conceptualization, writing—review and editing, visualization, supervision, funding acquisition.
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Maeda, N., Shimizu, S., Takahashi, Y. et al. Oral Exposure to Lead Acetate for 28 Days Reduces the Number of Neural Progenitor Cells but Increases the Number and Synaptic Plasticity of Newborn Granule Cells in Adult Hippocampal Neurogenesis of Young-Adult Rats. Neurotox Res 40, 2203–2220 (2022). https://doi.org/10.1007/s12640-022-00577-5
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DOI: https://doi.org/10.1007/s12640-022-00577-5