Diethylstilbestrol alters the population dynamic of neural precursor cells in the neonatal male rat dentate gyrus

Abstract

Little is known about how estrogens influence neurogenesis in the newborn male rodent. Herein, we examined the effects of neonatal diethylstilbestrol (DES) exposure on the proliferation and survival of type-1 and type-2 neural precursor cells (NPC) in the dentate gyrus of male rats. This was achieved by exposing newborn male pups to DES on postnatal day (PND) 1, PND3, PND5, and PND7, sacrificed at PND8 or PND21, followed by double immunohistochemistry and morphometric analysis of hippocampal dentate gyrus. Furthermore, vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) mRNA expression was evaluated in hippocampal tissue blocks by real time RT-PCR. At PND8, the density of total proliferating NPC decreased in DES-treated animals. This reduction was due to a significant decrease in the mitotic rate of type-2 cells only, since type-1 NPCs did not show changes in the proliferation index. Type-2 NPCs expressed the cell-cycle inhibitor p27(kip1) and its expression was clearly augmented in the DES-treated group. Furthermore, the number of apoptotic cells in the dentate gyrus of DES-treated rats decreased. Surprisingly, DES treatment enhanced cell survival and increased NPCs proliferation when animals were examined 14 days after treatment. VEGF mRNA expression showed a positive correlation with NPCs proliferation and BDNF mRNA levels were higher in DES-treated animals at both time points examined. Collectively, these results indicate that hippocampal NPCs proliferation and survival is a critical target of DES exposure during the early postnatal period. VEGF and BDNF are proposed as key mediators of DES-induced NPC mitotic response.