Evaluation of Species Difference of Adverse Health Effect due to Trichloroethylene utilizing DNA chip.

利用 DNA 芯片评估三氯乙烯对健康不良影响的物种差异。

• 批准号: 16590483
• 负责人: NAKASHIMA Hiroshi
• 金额: $ 2.24万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590483/
• 关键词: 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

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 … More 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

将三氯乙烯（TCE）暴露于人肝细胞的方法与小鼠或大鼠肝细胞的暴露方法相同。我们正在做实验，关注肝细胞的情况。有时我们会遇到细胞状况方面的困难，例如粘附不良。在这种情况下我们不得不中断实验。通过贝叶斯定理将选择因处理而显着改变的基因探针。贝叶斯定理需要四个独立的实验。然而，由于上述情况，总数仍然是三个。因此，我们通过方差分析临时选择了显着变化的探针。分别选择一百六十四个探针和一百四十一个探针进行4小时和24小时处理。通过免费分析软磨损 MAPPFinder 对显着变化的探头进行了功能分析。由于 TCE 是一种非基因毒性致癌物，因此生存信号或细胞凋亡尤其令人感兴趣。在 4 小时的治疗中，分析显示 TRIM38 的诱导和 VAPA 的抑制。这两个基因是 NF-κB 的诱导剂。还观察到 TNFRSF10B 的抑制和 OPA1 的诱导。前者是TNF超家族成员TRAIL的膜受体，与细胞凋亡的外源途径相关。后者与线粒体的融合和裂变有关。 OPA1 的 siRNA 诱导细胞凋亡，该分子被认为是一种抗细胞凋亡因子。本研究的目的是判断人类对 TCE 的反应是否接近小鼠或大鼠。我们认为，根据基因通过生物学功能识别物种差异来判断这一点是合理的，而不是根据基因在数学上识别小鼠和大鼠。对此我们参考了连续1500mg/kg口服给药实验。通过使用基因本体论或通路分析的功能分析，我们鉴定了表现出物种特异性反应并且通常被诱导的基因。TGF-β信号转导的抑制是小鼠特有的，并且与脂肪酸代谢相关的基因的诱导在小鼠中更强。与补体和凝血相关的基因的抑制被认为是常见的反应。较少的