Induction of cellular senescence as a late effect and BDNF-TrkB signaling-mediated ameliorating effect on disruption of hippocampal neurogenesis after developmental exposure to lead acetate in rats. (30th May 2021)

• Record Type: Journal Article
• Authors: Yamashita, Risako; Takahashi, Yasunori; Takashima, Kazumi; Okano, Hiromu; Ojiro, Ryota; Tang, Qian; Kikuchi, Satomi; Kobayashi, Mio; Ogawa, Bunichiro; Jin, Meilan; Kubota, Reiji; Ikarashi, Yoshiaki; Yoshida, Toshinori; Shibutani, Makoto
• Is Part Of: Toxicology. Volume 456(2021)
• Publication Date: 2021-05-30
• Subjects: ARC activity-regulated cytoskeleton-associated protein -- BDNF brain-derived neurotrophic factor -- CALB2 calbindin-D-29K -- CD cluster of differentiation -- COX2 cyclooxygenase 2 -- CT threshold cycle -- DCX doublecortin -- DNT developmental neurotoxicity -- DW distilled water -- FOS Fos proto-oncogene, AP-1 transcription factor subunit -- GABA γ-aminobutyric acid -- GM germinal matrices -- γ-H2AX phosphorylated H2A histone family member X -- Gapdh glyceraldehyde-3-phosphate dehydrogenase -- GCL granule cell layer -- GD gestational day -- GFAP glial fibrillary acidic protein -- Hprt1 hypoxanthine phosphoribosyltransferase 1 -- Iba1 ionized calcium-binding adaptor molecule 1 -- IEG immediate-early gene -- IL interleukin -- MT-I/II metallothionein-I/II -- NeuN neuronal nuclei -- NPC neural progenitor cell -- NSC neural stem cell -- OECD Organisation for Economic Co-operation and Development -- Pb lead -- PbAc lead acetate -- PCNA proliferating cell nuclear antigen -- PFA paraformaldehyde -- PND postnatal day -- p-TrkB phosphorylated tropomyosin receptor kinase B -- PVALB parvalbumin -- p21WAF1/CIP1 cyclin-dependent kinase inhibitor 1A -- RELN reelin -- SGZ subgranular zone -- SOX2 SRY-box transcription factor 2 -- SST somatostatin -- TBR2 T-box brain protein 2 -- TUBB3 tubulin, beta 3 class III -- TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling; Lead acetate -- Oxidative stress -- Neuroinflammation -- Neurogenesis -- Cellular senescence -- Genotoxicity; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2021.152782
• Languages: English
• ISSNs: 0300-483X

Abstract

Highlights: Offspring brain sustained oxidative stress and neuroinflammation until adulthood. Granule cell lineage increased apoptosis and suppressed differentiation at weaning. Interneuron subpopulations facilitated granule cell differentiation in adulthood. Activation of BDNF-TrkB signaling facilitated the granule cell differentiation. Cellular senescence of SGZ cells was found at adulthood following Pb genotoxicity. Abstract: Lead (Pb) exposure causes cognitive deficits in children. The present study investigated the effect of developmental exposure to Pb acetate (PbAc) on postnatal hippocampal neurogenesis. Pregnant rats were administered drinking water containing 0, 2000, or 4000 ppm PbAc from gestational day 6 until day 21 post-delivery (weaning), and offspring were maintained without PbAc exposure until adulthood on postnatal day (PND) 77. There was a dose-related accumulation of Pb in the offspring brain at weaning, while Pb was mainly excreted in adulthood. In the hippocampus, metallothionein I/II immunoreactive (+) glia were increased through adulthood as a neuroprotective response to accumulated Pb, accompanied by increased astrocyte and microglia numbers in adulthood, suggesting sustained neural damage. Gene expression changes suggested elevated oxidative stress at weaning and suppression of the antioxidant system in adulthood, as well as continued neuroinflammatory responses. At weaning, granule cell apoptosis was increased and numbers of type-3 neural progenitor cells (NPCs) were decreased. By contrast, type-2a and type-2b NPCs were increased, suggesting suppressed differentiation to type-3 NPCs. In adulthood, there were increased numbers of immature granule cells. In the hilus of the dentate gyrus, somatostatin + interneurons were increased at weaning, while calbindin-D-29K + interneurons were increased throughout adulthood, suggesting a strengthened interneuron regulatory system against the suppressed differentiation at weaning. In the dentate gyrus, Bdnf, Ntrk2, and Chrna7 gene expression were upregulated and numbers of hilar TrkB + interneurons increased at weaning. These findings suggest activation of BDNF-TrkB signaling to increase somatostatin + interneurons and promote cholinergic signaling, thus increasing later production of immature granule cells. In adulthood, Pcna and Apex1 gene expression were downregulated and Chek1 and cyclin-dependent kinase inhibitor expression were upregulated. Furthermore, there was an increase in γ-H2AX + SGZ cells, suggesting induction of cellular senescence of SGZ cells due to Pb genotoxicity.