| Project/Area Number |
16590483
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hygiene
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| Research Institution | Keio University |
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Principal Investigator |
NAKASHIMA Hiroshi Keio University, School of Medicine, Department of Preventive Medicine and Public Health, Instructor, 医学部, 助手 (80217710)
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| Co-Investigator(Kenkyū-buntansha) |
OMAE Kazuyuki Keio University, Professor, 医学部, 教授 (60118924)
TAKEBAYASHI Toru Keio University, Professor, 医学部, 教授 (30265780)
SANO Yuri Keio University, Instructor, 医学部, 助手 (20338023)
YOSHIOKA Noriyuki Keio University, Instructor, 医学部, 助手 (70365229)
衛藤 憲人 慶應義塾大学, 医学部, 助手 (60365228)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Toxicogenomics / Trichloroethylene / Species Difference / Extrapolation / Risk Assessment / DNAチップ / ヒト初代培養肝細胞 / 発現プロファイル |
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| Research Abstract |
Exposure of trichloroethylene (TCE) to human hepatocytes was done in the same way as that to mouse or rat hepatocytes. We are doing experiments, paying attention to the condition of hepatocytes. We sometimes have difficulties in the cell condition such as bad adhesion. We are forced to interrupt the experiment in such a case. Significantly changed probes of the gene by the treatment will be selected by Bayes' theorem. Bayes' theorem requires four independent experiments. Total number, however, remains three due to circumstances mentioned above. Thus, we temporary selected significantly changed probes by ANOVA. One hundred sixty four probes and one hundred forty one probes were selected for 4 hr and 24 hr treatment, respectively. Functional analysis was done for significantly changed probes by a free analysis soft wear MAPPFinder. Because TCE is a non-genotoxic carcinogen, survival signal or apoptosis is especially a matter of interest. In the 4 hr treatment, the analysis revealed induc
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tion of TRIM38 and suppression of VAPA. These two genes are inducer of NF-kappaB. Suppression of TNFRSF10B and induction of OPA1 were also observed. The former is a membrane receptor of TRAIL, a member of TNF superfamily, and related with extrinsic pathway of apoptosis. The latter is related with fusion and fission of mitochondrion. siRNA of OPA1 induced apoptosis and this molecule is implicated as an anti-apoptotic factor.
The aim of the study is to judge weather human is close to mouse or rat with regard to response to TCE. We are thinking that it is reasonable to judge this based on genes identify species difference by biological function rather than genes mathematically discern mouse and rat. We referred to the consecutive 1500 mg/kg oral administration experiment for this matter. By functional analysis using Gene Ontology or pathway analysis, we identified genes that showed species specific response and were commonly induced Inhibition of TGF-beta signal transduction is specific to mouse and induction of genes related with fatty acid metabolism is stronger in mouse. Suppression of genes related with complement and coagulation is identified as common response. Less
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