In utero exposure to dioxin causes neocortical dysgenesis through the actions of p27Kip1
In utero exposure to dioxin causes neocortical dysgenesis through the actions of p27Kip1
复制标题
DOI：
10.1073/pnas.1002960107
复制
发表时间：
2010-08
期刊：
影响因子：
--
通讯作者：
T. Mitsuhashi;J. Yonemoto;H. Sone;Y. Kosuge;K. Kosaki;Takao Takahashi
中科院分区：
文献类型：
--
作者：
T. Mitsuhashi;J. Yonemoto;H. Sone;Y. Kosuge;K. Kosaki;Takao Takahashi
据报告，二恶英会产生各种不利影响，包括体外细胞周期失调以及啮齿动物在子宫内接触二恶英后空间学习和记忆受损。此外，接触二恶英类似物多氯二苯并呋喃或多氯联苯的母亲所生的儿童在认知功能方面存在发育障碍。在这里，我们表明，在子宫内暴露于二恶英在小鼠中改变神经祖细胞的分化模式，并导致非GABA能神经元的数量减少和较薄的深层新皮层。这种非GABA能神经元数量的减少被认为是由神经祖细胞核中细胞周期蛋白依赖性激酶抑制剂p27 Kip 1的积累引起的。为支持这一假设，缺乏p27 Kip 1的小鼠对宫内二恶英暴露不敏感。这些结果表明，环境污染物可能通过改变特定基因/蛋白（在我们的情况下，二恶英）的功能影响新皮层组织发生，通过改变p27 Kip 1的功能产生不利影响。
Dioxins have been reported to exert various adverse effects, including cell-cycle dysregulation in vitro and impairment of spatial learning and memory after in utero exposure in rodents. Furthermore, children born to mothers who are exposed to dioxin analogs polychlorinated dibenzofurans or polychlorinated biphenyls have developmental impairments in cognitive functions. Here, we show that in utero exposure to dioxins in mice alters differentiation patterns of neural progenitors and leads to decreased numbers of non-GABAergic neurons and thinner deep neocortical layers. This reduction in number of non-GABAergic neurons is assumed to be caused by accumulation of cyclin-dependent kinase inhibitor p27Kip1 in nuclei of neural progenitors. Lending support to this presumption, mice lacking p27Kip1 are not susceptible to in utero dioxin exposure. These results show that environmental pollutants may affect neocortical histogenesis through alterations of functions of specific gene(s)/protein(s) (in our case, dioxins), exerting adverse effects by altering functions of p27Kip1.