2009 Fiscal Year Final Research Report
Establishment of new toxicity test using mouse ES cells
| Project/Area Number |
20790407
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Applied pharmacology
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| Research Institution | National Research Institute for Child Health and Development |
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Principal Investigator |
KUSAKAWA Shinnji National Research Institute for Child Health and Development, 薬剤治療研究部, 共同研究員 (80462802)
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| Project Period (FY) |
2008 – 2009
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| Keywords | 医薬品副作用 / 薬物相互作用 |
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| Research Abstract |
The embryonic stem cell test (EST) is an in vitro toxicity assay that assesses the ability of drugs and chemical compounds to inhibit the differentiation of ES cells into cardiomyocytes, and has been validated as an in vitro developmental toxicity test. We have developed an assay system based on the conventional EST, and tested this in vitro system by evaluating the embryotoxicity of antidepressant drugs (SSRIs) which have been reported as in vivo teratogens. In our studies, we added a molecular endpoint of differentiation to the conventional EST and attempted to characterize the tissue-specific embryotoxicity of these drugs by analyzing the gene expression of the tissue-specific markers as well as by conducting a histological and immunocytochemical study in the mouse ES cell differentiation system. These analyses revealed that fluoxetine, a prototypical SSRI, has potent tissue-specific embryotoxicity. Since these corresponds with the known in vivo teratology of these drugs, we conclud
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ed that our assay system is useful for predicting the degree of embryotoxicity of teratogens, and that it can be used to estimate the in vivo embryotoxic effects of various medicines quickly and accurately. However, further improvements, such as addition of new endpoints and expansion of test system, are necessary for optimized embryotoxicity test method. Thus, we have adopted a neural ES cell differentiation assay and conducted qualitative and/or quantitative analysis of the extent of differentiation by means of a GFP or a luciferase reporter assay. We previously found that fluoxetine induced fluctuations of ectodermal marker gene expression during ES cells differentiation from embryoid bodies, suggesting that fluoxetine may affect neural tissue development. Therefore, we further investigated the effect of fluoxetine in differentiation from ES cells to neural cells using the stromal cell-derived inducing activity (SDIA) method in this study and revealed that fluoxetine predominantly promotes the expression of glial cell lineage genetic markers during neural differentiation. Less
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