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.

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.