Multilateral study on the fetal toxicity with regard to the maternal-placental-fetal axis

关于母体-胎盘-胎儿轴胎儿毒性的多边研究

• 批准号: 16380206
• 负责人: UETSUKA Koji
• 金额: $ 9.86万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16380206/
• 关键词: fetal toxicity; placental toxicity; cell cycle; apoptosis; neural progenitor cell; p53 gene; environmental chemicals; CYP; 胎児中枢神経障害; 5-azacytidine; hydroxyurea; etoposide; p53; 5AzC; CYP inducer; T-2toxin; 胎盤; 母体肝臓; 胎児肝臓; 妊娠動物; 胎児脳; E

In order to elucidate molecular mechanisms of fetal toxicities caused by environmental chemicals, we performed multilateral analyses, considering the maternal-placental-fetal axis as a unit.We clarified gene expression profiles in the repair stage of fetal brain injury caused by ethylnitrosourea. 5-azacytidine administration developed both p53-dependent and -independent toxic injuries in the fetal brain, and the brain had the capacity to repair from the injuries. Hydroxyurea and VP-16 induced p53-related cell cycle arrest and further apotosis in the fetal mouse brain. Cytosine arabinoside also induced apoptosis in the placenta by the same mechanism in the fetal brain.We then examined the expression of drug-metabolizing enzymes in the pregnant rat liver. The expressions of CYP isozymes were suppressed in the gestation period, but they recovered in the weaning period. In the pregnant rats administered with CYP-inducers, the expression profile of phase II drug-metabolizing-related genes was similar to that of phase I genes in the placenta and maternal and fetal livers.T-2 toxin induced apoptosis in the placenta and maternal and fetal livers, in which the oxidative stress-induced activation of MEKK1-JNK-c-Jun pathway may play an important role.By the results of the present study, the effects of the toxic chemicals, not only direct effects to fetuses but those to the placenta, and the changes of drug metabolism in maternal liver in the gestation period, were clearly demonstrated. As fetal toxicity of a chemical is so much complex, multilateral analyses are very important.

为了阐明环境化学物质对胎儿毒性的分子机制，我们以母体-胎盘-胎儿轴为单位进行了多方面分析，阐明了乙基亚硝基脲致胎儿脑损伤修复阶段的基因表达谱。5-氮胞苷给药在胎儿脑中产生了p53依赖性和非依赖性毒性损伤，并且脑具有从损伤中修复的能力。羟基脲和VP-16诱导胎鼠脑中p53相关的细胞周期停滞和进一步的细胞凋亡。阿糖胞苷也通过胎脑中相同的机制诱导胎盘中的细胞凋亡。然后我们检测了孕鼠肝脏中药物代谢酶的表达。在妊娠期，两种同工酶的表达均受到抑制，但在断奶期又有所恢复。在CYP诱导剂妊娠大鼠中，胎盘和母胎肝中II相药物代谢相关基因的表达谱与I相基因的表达谱相似，T-2毒素诱导胎盘和母胎肝细胞凋亡，其中氧化应激诱导的MEKK 1-JNK-c-Jun通路的激活可能起重要作用。毒性化学品的影响，不仅对胎儿的直接影响，而且对胎盘的影响，以及妊娠期母体肝脏中药物代谢的变化，都得到了清楚的证明。由于化学品的胎儿毒性非常复杂，因此多边分析非常重要。

项目成果

Cell cycle and cell death regulation of neural progenitor cells in the 5-azacytidine (5AzC)-treated developing fetal brain

• DOI: 10.1016/j.expneurol.2005.11.024
• 发表时间: 2006-03
• 期刊: Experimental Neurology
• 影响因子: 5.3
• 作者: M. Ueno;K. Katayama;H. Yamauchi;H. Nakayama;K. Doi

Microarray analysis on CYPs expression in pregnant rats after treatment with pregnerolone-16alpha-carbonitrite and Phenobarbital

孕鼠酮-16α-亚硝酸盐和苯巴比妥治疗后妊娠大鼠CYPs表达的微阵列分析

• 发表时间: 2005
• 期刊: Exp.Mol.Pathol. 78
• 作者: Sehata S.;Kiyosawa N.;Atsumi F.;Ito K.;Yamoto T.;Teranishi M.;Uetsuka K.;Nakayama H.;Doi K.;Katayama K. et al.;Ejiri N. et al.
• 通讯作者: Ejiri N. et al.

Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced trophoblastic cell apoptosis and impaired proliferation in rat placenta.

p53 参与 1-β-D-阿拉伯呋喃糖基胞嘧啶诱导的大鼠胎盘滋养层细胞凋亡和增殖受损。

• 发表时间: 2004
• 期刊: Biol.Reprod. 70
• 作者: Yamauchi H.;et al.;Yamauchi H. et al.
• 通讯作者: Yamauchi H. et al.

Molecular mechanisms of hydroxyurea (HU)-induced apoptosis in the mouse

羟基脲（HU）诱导小鼠细胞凋亡的分子机制

• 发表时间: 2006
• 期刊: Neurotox. Teratol. 28
• 作者: Woo G.H.;et al.
• 通讯作者: et al.

Microarray analysis on CYPs expression in pregnant rats after treatment with pregnenolone-16 α-carbonitrile and phenobarbital.

孕烯醇酮-16α-甲腈和苯巴比妥治疗后妊娠大鼠CYPs表达的微阵列分析。

• 发表时间: 2005
• 期刊: Exp. Mol. Pathol. 78
• 作者: Ejiri N.;et al.
• 通讯作者: et al.