Proposal Abstract Depression affects many women of reproductive age, and it needs to be treated adequately during as well as before pregnancy to maintain maternal and fetal health. However, teratogenic potentials of common antidepressants, such as selective serotonin reuptake inhibitors (SSRI), are still unclear and controversial. Teratogenicity of drugs is strongly influenced by their concentrations that are exposed to developing embryos. However, how much of medications were actually taken during the critical stages of pregnancy is largely unclear in epidemiologic studies. Hence, it is difficult to evaluate dose-effect relationship, which may be contributing to the conflicting data on SSRI teratogenicity. Another unresolved issue is regarding the mechanism by which SSRI exert teratogenic potential. The therapeutic action of SSRI is to inhibit the serotonin transporter to elevate the neurotransmitter serotonin. However, it is still unclear whether the serotonin transporter plays crucial roles in embryo development. These issues need to be resolved to better understand the teratogenic potential of SSRI. The goal of the proposed project is to elucidate the molecular properties of common SSRI antidepressants, specifically on the concentration-adverse effect relationship and molecular targets that are pertinent to teratogenicity, using the novel assay platform of human embryonic stem (ES) cells that my lab established. Specifically, we will (1) determine exposure levels of SSRI that impact human stem cell development, (2) test the hypothesis that teratogenic effects of SSRI are due to inhibition of WNT signaling, and (3) test whether the therapeutic target molecule of SSRI is dispensable for teratogenicity. These studies should yield valuable information on teratogenic potential of SSRI, which will help in the design of more focused studies in human and in interpreting epidemiologic data.
Proposal Narrative The research goal is to investigate potential teratogenicity of common antidepressants that are prescribed to women of reproductive age, using a novel embryo development model created from human pluripotent stem cells. The findings will help in the design of more effective studies with human and animals to determine pregnancy risks of antidepressants.
