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

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Abstract

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 μM and 4.67 μM, respectively, and the ID50 value for ES cells was 3.79 μM. These results indicate that fluoxetine has strong toxicity evaluated by a mouse embryonic stem 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.

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