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


METHODS
Using a mouse embryonic stem (ES) cell differentiation system, we evaluated cell viability and differentiation affected by fluoxetine.


RESULTS
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 microM and 4.67 microM, respectively, and the ID50 value for ES cells was 3.79 microM. 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.


CONCLUSIONS
These results using the in vitro ES cell assay system suggest a possible relationship between the teratogenicity of fluoxetine and its molecular mechanism.
Kusakawa
Shinji
S
Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.
Yamauchi
Junji
J
Miyamoto
Yuki
Y
Sanbe
Atsushi
A
Tanoue
Akito
A
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005473:Fluoxetine / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D041681:NIH 3T3 Cells; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*
D015415:Biomarkers; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors