| Project/Area Number |
16380206
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied veterinary science
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| Research Institution | The University of Tokyo |
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Principal Investigator |
UETSUKA Koji (2006) The University of Tokyo, Graduate School of agricultural and Life Sciences, Assistant, 大学院農学生命科学研究科, 助手 (60251419)
土井 邦雄 (2004-2005) 東京大学, 大学院・農学生命科学研究科, 教授 (70155612)
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| Co-Investigator(Kenkyū-buntansha) |
KUMAGAI Susumu The University of Tokyo, Graduate School of agricultural and Life Sciences, Professor, 大学院農学生命科学研究科, 教授 (60109965)
ONODERA Takashi The University of Tokyo, Graduate School of agricultural and Life Sciences, Professor, 大学院農学生命科学研究科, 教授 (90012781)
SHIOTA Kunio The University of Tokyo, Graduate School of agricultural and Life Sciences, Professor, 大学院農学生命科学研究科, 教授 (80196352)
NAKAYAMA Hiroyuki The University of Tokyo, Graduate School of agricultural and Life Sciences, Professor, 大学院農学生命科学研究科, 教授 (40155891)
上塚 浩司 東京大学, 大学院・農学生命科学研究科, 助手 (60251419)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2005: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2004: ¥8,700,000 (Direct Cost: ¥8,700,000)
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| Keywords | 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 / Ethylnitrosourea / 胎児中枢神経傷害 / マイクロアレイ解析 / Ara-C / CYP inducers |
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| Research Abstract |
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.
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