Establishment of a 3D multicellular placental microtissues for investigating the effect of antidepressant vortioxetine.

The placenta is a unique organ with an active metabolism and dynamically changing physiology throughout pregnancy. It is difficult to elucidate the structure of cell-cell and cell-extracellular matrix interactions of the placenta in in vivo studies due to interspecies differences and ethical constraints. In this study, human umbilical cord vein cells (HUVEC) and human placental choriocarcinoma cells (BeWo) were co-cultured for the first time to form spheroids (microtissues) on a three-dimensional (3D) Petri Dish® mold and compared with a traditional two-dimensional (2D) system. Vortioxetine is an antidepressant with a lack of literature on its use in pregnancy in established cultures, the toxicity of vortioxetine was studied to investigate the response of spheroids representing placental tissue. Spheroids were characterised by morphology and exposed to vortioxetine. Cell viability and barrier integrity were then measured. Intercellular junctions and the localisation of serotonin transporter (SERT) proteins were demonstrated by immunofluorescence (IF) staining in BeWo cells. Human chorionic gonadotropin (beta-hCG) hormone levels were also measured. In the 3D system, cell viability and hormone production were higher than in the 2D system. It was observed that the barrier structure was impaired, the structure of intracellular skeletal elements was altered and SERT expression decreased depending on vortioxetine exposure. These results demonstrate that the multicellular microtissue placenta model can be used to obtain results that more closely resemble in vivo toxicity studies of various xenobiotics than other 2D and mono-culture spheroid models in the literature. It also describes the use of 3D models for soft tissues other than the placenta.

Toxicity of waterborne vortioxetine, a new antidepressant, in non-target aquatic organisms: From wonder to concern drugs?

Vortioxetine is increasing in popularity as a treatment for major depressive disorder and has been detected in wastewater effluent. However, information on the toxicity and environmental risk of vortioxetine in non-target organisms is scarce. Here, embryonic and juvenile zebrafish (Danio rerio) were used to assess the toxicity of vortioxetine (0, 1, 10, 30, 100, 300, and 1000 µg/L) after 120 h and 7 d of exposure, respectively. Vortioxetine induced significant toxicity during embryonic development, including effects on survival, hatching, basal heart rate, spontaneous tail coiling and developmental abnormalities, and inhibited larval locomotor activity at concentrations higher than 30 µg/L. Additionally, vortioxetine evoked anxiolytic-like behavior and caused histopathological changes to multiple organs (gills, heart, liver and intestine) in juvenile zebrafish. Significant increase in 5-HT content was observed in whole zebrafish larvae and juvenile brain tissues from animals treated with 1 or 100 µg/L vortioxetine. Notably, the lowest effective concentrations of vortioxetine for zebrafish were mainly in the range of 10-30 µg/L, which were slightly lower than the vortioxetine therapeutic concentrations. Risk quotients assuming conservative exposure assessments were above one in European countries indicating moderate risk for the behavioral endpoints assessed. We believe that these results highlight the adverse effects of vortioxetine on non-target organisms and that further investigations will be required to provide a higher confidence.