Toxic effects of in utero exposure to dioxins on cerebral histogenesis: quantitative analysis using mathematical model of cerebral histogenesis.

子宫内接触二恶英对脑组织发生的毒性作用：使用脑组织发生数学模型进行定量分析。

• 批准号: 15390327
• 负责人: TAKAHASHI Takao
• 金额: $ 9.28万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390327/
• 关键词: cortical histogenesis; in utero exposure; neuronal progenitor cells; mouse; differentiation; cell cycle; p27Kip1; TCDD; p27Kip1; ダイオキシン

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental pollutant known to disturb hormonal homeostasis as well as more fundamental cell proliferative behavior. Among the recognized specific effects upon histogenesis due to exposure to TCDD in utero are impairment of development of immune and urogenital systems in mice and impairment of thyroid function. With respect to cellular proliferative behavior, TCDD inhibits G1 phase progression by inducing p27Kip1 expression in a hepatoma cell line and in fetal thymocytesis In rodents exposure to TCDD in utero may be associated with impaired spatial learning and memory. The cell biological basis for this impairment and its consequences for CNS histogenesis are unknown. Because cell cycle kinetics is critically controlled at the G1 restriction point by the action of p27Kip1, we consider that TCDD exposure may act upon this regulatory mechanism, at least in part, to disturb cerebral histogenesis.We have investigated the conseque … More nce of TCDD exposure in utero on embryonic day (E) 7 upon cerebral histogenesis, by examining the cytoarchitecture of the postnatal day 21 brain and developing cerebral wall and cell cycle kinetics of the PVE at E12.MethodWe exposed C57BL/6N mice fetus with TCDD by oral gavage (20 μg/kg body weight) at E7. We analyzed 1.mRNA expression level and subcellular localization pattern of cell cycle regulatory genes, 2.length of each phase of cell cycle, 3.probability of differentiation (Q) in neuronal progenitor cells (NPC) at E12. Additionally, we measured 1.size of telencephalon, 2.thickness of cortices, 3.numbers and densities of GABA-positive, negative neurons and glial cells, respectively, in layer specific manner at P21 mice.ResultIn utero exposure to TCDD resulted in 1.increase in p27Kip1 protein level in nuclei, 2.increase in length of G1 phase of cell cycle, 3.increase in Q in NPC at E12. TCDD-exposed P21 telencephalon showed decrease in length, width, and cortical thickness. This cortical thinning was mainly due to decrease in number of non-GABAergic projection neurons in layer V-VIDiscussionTCDD exposure in utero resulted in abnormal cortical histogenesis (decreased thickness of neocortex). We speculate that TCDD exposure increased p27Kip1 protein in nuclei of NPC that lead to increase in both G1 phase and Q. Thus premature increase in Q decrease the total output of projection neurons in the neocotex by decreasing the maximum number of NPC in the course of neuronogenesis. We speculate that decrease in number of projection neurons in layer V-VI in TCDD exposed mice might be resulted from premature switch of neuronal fate from deep layer to superficial neuronal phenotype by abnormal increase in Q fraction by TCDD exposure. Less

2，3，7，8-四氯二苯并-对-二恶英（TCDD）是一种普遍存在的环境污染物，已知其干扰激素稳态以及更基本的细胞增殖行为。在子宫内暴露于TCDD对组织发生的公认的特定影响中，包括小鼠免疫和泌尿生殖系统发育受损以及甲状腺功能受损。关于细胞增殖行为，TCDD通过诱导肝癌细胞系和胎儿胸腺细胞增多中p27 Kip 1的表达来抑制G1期进展。在啮齿类动物中，子宫内暴露于TCDD可能与空间学习和记忆受损有关。这种损伤的细胞生物学基础及其对CNS组织发生的影响尚不清楚。由于细胞周期动力学在G1限制点受到p27 Kip 1作用的关键控制，我们认为TCDD暴露可能作用于这一调节机制，至少部分干扰脑组织发生。 ...更多信息 通过观察出生后21天脑的细胞结构和E12时PVE发育中的脑壁细胞和细胞周期动力学，探讨TCDD在胚胎7天宫内暴露对脑组织发生的影响。我们分析了1.mRNA表达水平和细胞周期调控基因的亚细胞定位模式，2.细胞周期各时相的长度，3.在E12的神经元祖细胞（NPC）的分化概率（Q）。结果TCDD宫内染毒可引起鼻咽癌细胞核内p27 Kip 1蛋白表达增加，细胞周期G1期延长，Q值增加，并可引起鼻咽癌细胞凋亡。TCDD暴露的P21端脑的长度，宽度和皮质厚度减少。这种皮层变薄主要是由于V-VI层非GABA能投射神经元数量减少。我们推测TCDD暴露可增加鼻咽癌细胞核中p27 Kip 1蛋白的表达，从而导致G1期和Q期的增加。因此，过早地增加Q值会通过减少神经元发生过程中NPC的最大数量来减少新皮层投射神经元的总输出。我们推测，TCDD暴露小鼠V-VI层投射神经元数量的减少可能是由于TCDD暴露导致Q分数异常增加，导致神经元命运从深层过早转变为表层神经元表型所致。少

项目成果

Role of Rho-kinase and p27 in Angiotensin Il-Induced Vascular Injury.

Rho 激酶和 p27 在血管紧张素 II 诱导的血管损伤中的作用。

• 发表时间: 2005
• 期刊: Hypertension 45・4
• 作者: Nagasawa M;Mizutani S et al.;辻浩一郎 他;Kamezaki K;Kanda T
• 通讯作者: Kanda T

Yahagi N: "Position-specific expression of Hox genes along the gastrointestinal tract."Congenital Anomalies. 44. 18-26 (2004)

Yahagi N：“Hox 基因在胃肠道中的位置特异性表达。”先天性异常。

高橋孝雄: "皮質形成異常"小児疾患診療のための病態生理2、小児内科. 35. 593-597 (2003)

Takao Takahashi：“皮质发育不良”儿科疾病治疗的病理生理学2，儿科内科医学35。593-597（2003）。

In utero dioxin (TCDD) exposure causes neocortical dysgenesis : coordinate regulation of probability of cell cycle exit and laminar fate of neocortical neurons.

子宫内二恶英（TCDD）暴露导致新皮质发育不全：细胞周期退出概率和新皮质神经元层状命运的协调调节。

• 发表时间: 2004
• 期刊: 2004 Abstract Viewer/Itinerary Planner. Washington, DC : Society for Neuroscience 30
• 作者: Mitsuhashi T

RNA-binding protein HuD regulates neuronal cell identity and maturation.

RNA 结合蛋白 HuD 调节神经元细胞的身份和成熟。

• 发表时间: 2005
• 期刊: Proc Natl Acad Sci USA. 102
• 作者: Iijima T;Imai T;Kimura Y;Bernstein A;Okano HJ;Yuzaki M;Okano H;Yano M.et al.;Akamatsu W. et al.
• 通讯作者: Akamatsu W. et al.