title: Fluoxetine and its active metabolite norfluoxetine disrupt estrogen synthesis in a co-culture model of the feto-placental unit.
abstract: The effects of fluoxetine, one of the most prescribed selective serotonin-reuptake inhibitors (SSRIs) during pregnancy, and its active metabolite norfluoxetine were studied on placental aromatase (CYP19) and feto-placental steroidogenesis. Fluoxetine did not alter estrogen secretion in co-culture of fetal-like adrenocortical (H295R) and trophoblast-like (BeWo) cells used as a model of the feto-placental unit, although it induced CYP19 activity, apparently mediated by the serotonin (5-HT)2Areceptor/PKC signaling pathway. Norfluoxetine decreased estrogen secretion in the feto-placental co-culture and competitively inhibited catalytic CYP19 activity in BeWo cells. Decreased serotonin transporter (SERT) activity in the co-culture was comparable to 17β-estradiol treatment of BeWo cells. This work shows that the complex interaction of fluoxetine and norfluoxetine with placental estrogen production, involves 5-HT-dependent and -independent mechanisms. Considering the crucial role of estrogens during pregnancy, our results raise concern about the impact of SSRI treatment on placental function and fetal health.
authors.affiliation: INRS-Institut Armand-Frappier, 531, Boul. des Prairies, Laval, QC, H7V 1B7, Canada; BioMed Research Centre, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, QC, H3C 3P8, Canada; Center for Interdisciplinary Research on Well-Being, Health, Society and Environment (CINBIOSE), Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, QC, H3C 3P8, Canada.
authors.forename: Andrée-Anne
authors.initials: AA
authors.lastname: Hudon Thibeault
authors.affiliation: INRS-Institut Armand-Frappier, 531, Boul. des Prairies, Laval, QC, H7V 1B7, Canada; BioMed Research Centre, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, QC, H3C 3P8, Canada; Center for Interdisciplinary Research on Well-Being, Health, Society and Environment (CINBIOSE), Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, QC, H3C 3P8, Canada.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Laurent
authors.affiliation: Department of Chemistry, University of Montreal, C.P. 6128 Succ. Centre-ville, Montréal, QC, H3C 3J7, Canada.
authors.forename: Sung
authors.initials: S
authors.lastname: Vo Duy
authors.affiliation: Department of Chemistry, University of Montreal, C.P. 6128 Succ. Centre-ville, Montréal, QC, H3C 3J7, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Sauvé
authors.affiliation: Laboratoire de Pharmacogénomique, Faculté de Pharmacie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, 2705 Boul. Laurier, Local T3-48, Québec, QC, G1V 4G2, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Caron
authors.affiliation: Laboratoire de Pharmacogénomique, Faculté de Pharmacie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, 2705 Boul. Laurier, Local T3-48, Québec, QC, G1V 4G2, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
authors.affiliation: INRS-Institut Armand-Frappier, 531, Boul. des Prairies, Laval, QC, H7V 1B7, Canada. Electronic address: thomas.sanderson@iaf.inrs.ca.
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Sanderson
authors.affiliation: INRS-Institut Armand-Frappier, 531, Boul. des Prairies, Laval, QC, H7V 1B7, Canada; BioMed Research Centre, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, QC, H3C 3P8, Canada; Center for Interdisciplinary Research on Well-Being, Health, Society and Environment (CINBIOSE), Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, QC, H3C 3P8, Canada. Electronic address: cathy.vaillancourt@iaf.inrs.ca.
authors.forename: Cathy
authors.initials: C
authors.lastname: Vaillancourt
mesh_terms: D001141:Aromatase / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques / Q000379:methods; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001141:Aromatase; D004958:Estradiol; D004967:Estrogens; D005473:Fluoxetine; D026901:Membrane Transport Proteins; D011493:Protein Kinase C; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C036139:norfluoxetine
keywords: 5-HT(2A) receptor; Aromatase (CYP19); Feto-placental steroidogenesis; Human; Selective serotonin-reuptake inhibitors (SSRI); Serotonin transporter (SERT)