The evaluation of early embryonic neurogenesis after exposure to the genotoxic agent 5-bromo-2'-deoxyuridine in mice
The evaluation of early embryonic neurogenesis after exposure to the genotoxic agent 5-bromo-2'-deoxyuridine in mice
复制标题
DOI：
10.1016/j.neuro.2006.07.017
复制
发表时间：
2007-07-01
期刊：
影响因子：
3.4
通讯作者：
Shioda, Seiji
中科院分区：
文献类型：
--
作者：
Kuwagata, Makiko;Ogawa, Tetsuo;Shioda, Seiji
发育性神经毒性（DNT）是儿童健康的重要问题。神经发生在整个早期胎儿到产后时期。胚胎干细胞的增殖可以成为毒物的靶标，尤其是遗传毒性化合物。5-溴-2 '-脱氧尿苷（BrdU），一种胸苷类似物，已被用作增殖细胞的标记物。然而，我们报告说，产前BrdU暴露诱导行为异常，如多动的大鼠和小鼠后代。在这项研究中，为了进一步阐明BrdU对早期神经发生的毒性作用，并检查该过程在DNT中的评价的有用性，C57 BL/6小鼠在妊娠第9或11天暴露于100 mg/kg的BrdU，并在暴露后24 h检查了胚胎大脑各种区域的连续切片。BrdU暴露于GD 11诱导细胞死亡，在一些特定的领域，如新皮质和纹状体，但不是在黑质，中缝和脑桥，即使BrdU被纳入这些细胞。BrdU降低了皮质、乳头体和小脑中磷酸化组蛋白3（磷酸化组蛋白3）阳性细胞的数量，磷酸化组蛋白3是有丝分裂中期增殖细胞的标志物，表明BrdU影响神经干细胞的增殖。GD 9暴露未诱导胎仔脑细胞死亡。这些结果表明，BrdU实际上损害了早期的神经发生，支持出生后的结果，并证明胚胎神经发生具有异质性的敏感性，根据不同的区域和发育阶段的遗传毒性剂BrdU。早期神经发生事件的评价，如神经干细胞的增殖后不久，化学暴露将是一个有价值的终点研究出生后神经发育障碍。(c)2006年爱思唯尔公司All rights reserved.
Developmental neurotoxicity (DNT) is an important issue in children's health. Neurogenesis occurs throughout the early fetal to the postnatal period. The proliferation of embryonic stem cells can be a target for toxicants, especially genotoxic compounds.5-Bromo-2 '-deoxyuridine (BrdU), a thymidine analogue, has been used as a marker for proliferating cells. However, we reported that prenatal BrdU exposure induced behavioral abnormalities such as hyperactivity in rat and mouse offspring. In this study, to further clarify the toxic effect of BrdU on the early neurogenesis and to examine the usefulness of the evaluation of this process in DNT, C57BL/6 mice were exposed to 100 mg/kg of BrdU once on gestational day (GD) 9 or 11, and serial sections from a wide variety of areas of the embryonic brains 24 h after the exposure were examined. BrdU exposure on GD11 induced cell death in some specific areas, such as the neocortex and striatum, but not in the substantia nigra, raphe and pons, even though BrdU was incorporated into those cells. BrdU decreased the number of cells positive for phosphorylated histone 3 (phospho-hi stone 3), a marker for proliferating cells at metaphase of mitosis, in the cortex, mammillary body and cerebellum, suggesting that BrdU affected the proliferation of neural stem cells. Exposure on GD9 did not induce cell death in the fetal brain. These results indicate that BrdU actually impaired the early neurogenesis, supporting the postnatal results, and demonstrated that embryonic neurogenesis has heterogeneous sensitivity to the genotoxic agents BrdU that differs according to the area and developmental stage. The evaluation of events in early neurogenesis such as the proliferation of neural stem cells shortly after chemical exposure will be one of the valuable endpoints for studying postnatal neurodevelopmental disorders. (c) 2006 Elsevier Inc. All rights reserved.