Fluoxetine and its active metabolite norfluoxetine disrupt estrogen synthesis in a co-culture model of the feto-placental unit. (15th February 2017) - Hudon Thibeault, Andrée-Anne
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)2A receptor/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. Graphical abstract: Proposed mode of action of the antidepressant fluoxetine on estrogen synthesis in human placental BeWo cells. Fluoxetine stimulates serotonin 5-HT2A receptor either by inhibiting serotonin transporter (SERT) and increasing serotonin (5-HT) extracellular levels or by stimulating directly 5-HT2A and then phospholipase C/protein kinase C (PLC/PKC) pathway to induce CYP19 activity. In turn, estrogens inhibit SERT activity. Norfluoxetine inhibits CYP19 catalytic activity, decreasing estrogen secretion. Highlights: Fluoxetine induces aromatase (CYP19) activity in a feto-placental co-culture model. Norfluoxetine is a competitive inhibitor of CYP19 in human placental BeWo cells. In the feto-placental model, norfluoxetine decreases estrogen secretion. In the feto-placental model, fluoxetine is without effect on estrogen secretion. Fluoxetine and 17β-estradiol inhibit serotonin transporter activity in BeWo cells.