Differences and Interactions in Placental Manganese and Iron Transfer across an In Vitro Model of Human Villous Trophoblasts.

Manganese (Mn) as well as iron (Fe) are essential trace elements (TE) important for the maintenance of physiological functions including fetal development. However, in the case of Mn, evidence suggests that excess levels of intrauterine Mn are associated with adverse pregnancy outcomes. Although Mn is known to cross the placenta, the fundamentals of Mn transfer kinetics and mechanisms are largely unknown. Moreover, exposure to combinations of TEs should be considered in mechanistic transfer studies, in particular for TEs expected to share similar transfer pathways. Here, we performed a mechanistic in vitro study on the placental transfer of Mn across a BeWo b30 trophoblast layer. Our data revealed distinct differences in the placental transfer of Mn and Fe. While placental permeability to Fe showed a clear inverse dose-dependency, Mn transfer was largely independent of the applied doses. Concurrent exposure of Mn and Fe revealed transfer interactions of Fe and Mn, indicating that they share common transfer mechanisms. In general, mRNA and protein expression of discussed transporters like DMT1, TfR, or FPN were only marginally altered in BeWo cells despite the different exposure scenarios highlighting that Mn transfer across the trophoblast layer likely involves a combination of active and passive transport processes.

Tributyltin and triphenyltin induce 11ß-hydroxysteroid dehydrogenase 2 expression and activity through activation of retinoid X receptor α.

Exposure to the environmental pollutants organotins is of toxicological concern for the marine ecosystem and sensitive human populations, including pregnant women and their unborn children. Using a placenta cell model, we investigated whether organotins at nanomolar concentrations affect the expression and activity of 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 11ß-HSD2 represents a placental barrier controlling access of maternal glucocorticoids to the fetus. The organotins tributyltin (TBT) and triphenyltin (TPT) induced 11ß-HSD2 expression and activity in JEG-3 placenta cells, an effect confirmed at the mRNA level in primary human trophoblast cells. Inhibition/knock-down of retinoid X receptor alpha (RXRα) in JEG-3 cells reduced the effect of organotins on 11ß-HSD2 activity, mRNA and protein levels, revealing involvement of RXRα. Experiments using RNA and protein synthesis inhibitors indicated that the effect of organotins on 11ß-HSD2 expression was direct and caused by increased transcription. Induction of placental 11ß-HSD2 activity by TBT, TPT and other endocrine disrupting chemicals acting as RXRα agonists may affect placental barrier function by altering the expression of glucocorticoid-dependent genes and resulting in decreased availability of active glucocorticoids for the fetus, disturbing development and increasing the risk for metabolic and cardiovascular complications in later life.

Investigating the accumulation and translocation of titanium dioxide nanoparticles with different surface modifications in static and dynamic human placental transfer models.

Titanium dioxide nanoparticles (TiO2 NPs) are widely incorporated in various consumer products such as cosmetics and food. Despite known human exposure, the potential risks of TiO2 NPs during pregnancy are not fully understood, but several studies in mice elucidated toxic effects on fetal development. It has also been shown that modifying NPs with positive or negative surface charge alters cellular uptake and abolishes fetotoxicity of silicon dioxide (SiO2) NPs in mice. Here, we investigated accumulation and translocation of positively charged TiO2-NH2 and negatively charged TiO2-COOH NPs at the placental barrier, to clarify whether surface charge provides a means to control TiO2 NP distribution at the placental barrier. To ensure outcome relevant for humans, the recently developed in vitro human placental co-culture model and the gold standard amongst placental translocation models - the ex vivo perfusion of human term placental tissue - were employed during this study. Sector field-ICP-MS analysis of maternal and fetal supernatants as well as placental cells/tissues revealed a substantial accumulation of both TiO2 NP types while no considerable placental translocation was apparent in both models. Characterization of agglomeration behavior demonstrated a strong and fast agglomeration of TiO2-NH2 and TiO2-COOH NPs in the different culture media. Overall, our results indicate that surface charge is not a key factor to steer placental uptake and transfer of TiO2. Moreover, the negligible placental transfer but high accumulation of TiO2 NPs in placental tissue suggests that potential effects on fetal health may occur indirectly, which calls for further studies elucidating the impact of TiO2 NPs on placental tissue functionality and signaling.