Estimation of embryotoxic effect of fluoxetine using embryonic stem cell differentiation system

Aims: Fluoxetine is an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) class, which is commonly prescribed to treat a wide spectrum of mood disorders including depression during pregnancy and lactation. Recent Studies have proposed a possible association between an increase in major malformations and the maternal use of SSRI drugs during pregnancy. Here, we assess the effects of fluoxetine using a mouse ES cell differentiation system to clarify the possible association. Main methods: Using a mouse embryonic stem (ES) cell differentiation system, we evaluated cell viability and differentiation affected by fluoxetine. Key findings: Fluoxetine adversely affected cell viability and differentiation from undifferentiated ES cells to cardiomyocytes in a dose-dependent manner. The IC50 Values of fluoxetine for ES cells and NIH-3T3 fibroblasts were 1.79 mu M and 4.67 mu M, respectively, and the ID50 value for ES cells was 3.79 mu M. These results indicate that fluoxetine has strong toxicity evaluated by a mouse embryonic stein cell test (EST). Analysis of tissue-specific markers revealed that fluoxetine potently inhibits mesodermal development. although it promotes ectodermal differentiation in a lineage-specific manner. Significance: These results using the in vitro ES cell assay system suggest a possible relationship between the teratogenicity of fluoxetine and its molecular mechanism. (C) 2008 Elsevier Inc. All rights reserved.