Ramos Jorge G, Varayoud Jorgelina, Monje Lucas, Moreno-Piovano Guillermo, Muñoz-de-Toro Mónica, Luque Enrique H
Laboratorio de Endocrinología y Tumores Hormonodependientes, School of Biochemistry and Biological Sciences, Universidad Nacional del Litoral, Casilla de Correo 242, 3000 Santa Fe, Argentina.
Brain Res Bull. 2007 Mar 30;71(6):619-27. doi: 10.1016/j.brainresbull.2006.12.004. Epub 2007 Jan 4.
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.
关于雌激素如何影响新生雄性啮齿动物的神经发生，目前所知甚少。在此，我们研究了新生期暴露于己烯雌酚（DES）对雄性大鼠齿状回中1型和2型神经前体细胞（NPC）增殖和存活的影响。通过在出生后第1天（PND）、PND3、PND5和PND7给新生雄性幼崽暴露于DES，在PND8或PND21处死，随后对海马齿状回进行双重免疫组织化学和形态计量分析来实现。此外，通过实时RT-PCR评估海马组织块中血管内皮生长因子（VEGF）和脑源性神经营养因子（BDNF）的mRNA表达。在PND8时，DES处理组动物中总增殖NPC的密度降低。这种降低仅归因于2型细胞有丝分裂率的显著下降，因为1型NPC的增殖指数没有变化。2型NPC表达细胞周期抑制剂p27（kip1），其在DES处理组中的表达明显增强。此外，DES处理大鼠齿状回中的凋亡细胞数量减少。令人惊讶的是，在处理14天后检查动物时，DES处理增强了细胞存活并增加了NPC的增殖。在两个检查时间点，DES处理组动物的VEGF mRNA表达与NPC增殖呈正相关，BDNF mRNA水平更高。总体而言，这些结果表明海马NPC的增殖和存活是出生后早期DES暴露的关键靶点。VEGF和BDNF被认为是DES诱导的NPC有丝分裂反应的关键介质。
