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Effects of fluoxetine on human embryo development
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Reproduktiv hälsa/Sundström Poromaa)
Centre of Reproduction, Uppsala University Hospital Uppsala, Sweden.
IVF-Clinic Falun Falun, Sweden.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
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2016 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 10, 160Article in journal (Other academic) Published
Abstract [en]

The use of antidepressant treatment during pregnancy is increasing, and selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressants in pregnant women. Serotonin plays a role in embryogenesis, and serotonin transporters are expressed in two-cell mouse embryos. Thus, the aim of the present study was to evaluate whether fluoxetine, one of the most prescribed SSRI antidepressant world-wide, exposure influences the timing of different embryo developmental stages, and furthermore, to analyze what protein, and protein networks, are affected by fluoxetine in the early embryo development. Human embryos (17 = 48) were randomly assigned to treatment with 0.25 or 0.5 IiM fluoxetine in culture medium. Embryo development was evaluated by time-lapse monitoring. The fluoxetine-induced human embryo proteome was analyzed by shotgun mass spectrometry. Protein secretion from fluoxetine-exposed human embryos was analyzed by use of high-multiplex immunoassay. The lower dose of fluoxetine had no influence on embryo development. A trend toward reduced time between thawing and start of cavitation was noted in embryos treated with 0.5 it M fluoxetine (p = 0.065). Protein analysis by shotgun mass spectrometry detected 45 proteins that were uniquely expressed in fluoxetine-treated embryos. These proteins are involved in cell growth, survival, proliferation, and inflammatory response. Culturing with 0.5 p M, but not 0.25 p M fluoxetine, caused a significant increase in urokinase-type plasminogen activator (uPA) in the culture medium. In conclusion, fluoxetine has marginal effects on the timing of developmental stages in embryos, but induces expression and secretion of several proteins in a manner that depends on dose. For these reasons, and in line with current guidelines, the lowest possible dose of SSRI should be used in pregnant women who need to continue treatment.

Place, publisher, year, edition, pages
2016. Vol. 10, 160
Keyword [en]
embryo development; selective serotonin reuptake inhibitors; serotonin; human; time-lapse monitoring; proteomics; secretomics; shotgun mass spectrometry
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Medical Science
URN: urn:nbn:se:uu:diva-242825DOI: 10.3389/fncel.2016.00160ISI: 000377967700001PubMedID: 27378857OAI: oai:DiVA.org:uu-242825DiVA: diva2:785285
Swedish Research Council, VR 621-2011-4423
Available from: 2015-02-02 Created: 2015-02-02 Last updated: 2016-08-15Bibliographically approved
In thesis
1. The Effects of SSRI Treatment on Human Placenta and Embryo
Open this publication in new window or tab >>The Effects of SSRI Treatment on Human Placenta and Embryo
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During pregnancy, 4 - 7% of women suffer from major depressive disorder. When antidepressive treatment is needed, selective serotonin reuptake inhibitors (SSRIs) are the most commonly used. Although severe complications from SSRI treatment are rare, association with a number of adverse pregnancy and fetal outcomes has been found. Also, antenatal depression per se has been shown to affect pregnancy outcomes. The overall aim of this thesis was to examine the effects of SSRIs on human placenta and embryo.

In the first study, gene expression was investigated in placenta from depressed, SSRI-treated and healthy pregnant women, using microarray analysis. Antenatal depression and SSRI treatment induced alterations in gene expression, but only 20 genes in common were noted. Validation with qRT-PCR showed that six out of seven selected genes were altered in SSRI-treated women compared with controls, and two genes were altered between depressed women and controls.

In study two, the protein levels in placenta from depressed, SSRI-treated and healthy pregnant women were investigated, focusing on the NGF signaling pathway. NGF, phosphorylated Raf-1, ROCK2 and phosphorylated ROCK2, were altered in both SSRI-treated and depressed women, although the proteins were regulated differently in the two groups.

In the third study, human embryos were treated with fluoxetine. Embryo development and protein expression were studied. Fluoxetine had some effect on the timing of embryo developmental stages. Also, several proteins were uniquely found in fluoxetine-treated embryos compared with untreated embryos. Fluoxetine also altered the levels of proteins secreted from the embryo.

In the fourth study, the human neuroblastoma cell line SH-SY5Y/TrkA was treated with TPA and NGF. The activation of Raf-1 was investigated and the involvement of Ras and PKC was studied. Both NGF and TPA activated Raf-1, but to a different extent and via different pathways. The NGF-induced activation of Raf-1 was mediated via Ras, while TPA induced signaling via PKC.

In conclusion, SSRI treatment and antenatal depression influence placental gene and protein expression. These findings may affect placental development and function, which in turn could affect fetal development. Also, direct exposure of embryos to fluoxetine has some effects on embryo development and protein expression, which may affect the development of the fetus.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 90 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1095
antenatal depression, embryo, embryo development, fluoxetine, gene expression, NGF, placenta, protein expression, Raf-1, ROCK, signaling pathways, SSRI
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Medical Science; Obstetrics and Gynaecology
urn:nbn:se:uu:diva-248527 (URN)978-91-554-9227-4 (ISBN)
Public defence
2015-05-28, Sal IV, Universitetshuset, Uppsala, 09:15 (Swedish)
Available from: 2015-05-06 Created: 2015-03-31 Last updated: 2015-07-07

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Kaihola, HelenaHörnaeus, KatarinaBergquist, JonasÅkerud, HelenaSundström-Poromaa, Inger
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Frontiers in Cellular Neuroscience
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