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。

基本信息

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

项目摘要

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

2,3,7,8-四氯二苯甲酸-P-二恶英（TCDD）是一种无处不在的环境抛光，已知会干扰荷尔蒙热线器，以及在utero中受到utero造成的更大的精神细胞增殖行为的影响。小鼠免疫和泌尿生殖器系统的发展以及甲状腺功能的损害。和记忆的损害的细胞生物学基础是CNS组织发生的后果，这是未知的。 E12的PVE动力学。Methodwe通过口服肿瘤暴露了带有TCDD的C57BL/6N小鼠胎儿，通过口服haly酸盐1.MRNA的表达水平和细胞哭泣基因的亚细胞定位模式，细胞的长度，细胞夹带的长度（Q）在神经祖细胞（NPC）（NPC）的长度（q） e12，我们测量1.端脑，2。皮层的厚度，3。p21小鼠的gaba阳性，负神经元和神经元的密度和密度p27KIP1蛋白水平在细胞周期的G1期长度上增加，在E12处NPC中的Q中crese酶。皮质组织发生异常（新皮层的厚度减少）。通过TCDD暴露的Q分数异常增加，神经元命运从Deeer到表面神经元表型

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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。

DOI：
发表时间：
2005
期刊：
Hypertension 45・4
影响因子：
0
作者：
Nagasawa M;Mizutani S et al.;辻浩一郎他;Kamezaki K;Kanda T
通讯作者：
Kanda T

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）。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

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。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

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。

DOI：
发表时间：
2005
期刊：
Proc Natl Acad Sci USA. 102
影响因子：
0
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.

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。