Progesterone and zinc regulate zinc transport in human trophoblasts through changes in Zip4 and ZnT1

Abstract

The trophoblast interfaces maternal and fetal nutrient exchange and thus regulates nutrient transfer to the offspring. Progesterone (PG) is critical for successful trophoblast implantation and fetal survival and has been recently recognized as exerting acute, non-genomic effects, potentially through a membrane-associated PG receptor. While zinc (Zn) is an essential trace element needed for normal fetal growth and development, mechanisms regulating trophoblast Zn transport are not understood. We hypothesize that Zip4 (Zn import) and ZnT1 (Zn export) regulate Zn transport across the trophoblast. The objective of this study was to determine acute regulation of Zn transport by Zn and PG in cultured human trophoblast (BeWo) cells. Progesterone (1 μM) reduced total Zn transport (4-fold) resulting from decreased basolateral Zn efflux (1.5-fold) through reduced ZnT1 abundance, and increased cellular Zn retention (3-fold) through greater Zip4 abundance. Confocal microscopy and Western blotting localized Zip4 and ZnT1 to the plasma membrane (PM). While PG increased Zip4 abundance at the PM, ZnT1 abundance at the PM was reduced. These non-genomic effects were likely mediated by membrane-associated PG receptors, identified at ~116 and 81 kDa. In contrast, Zn (50 μM) decreased cellular Zn retention (2-fold) which was associated with increased ZnT1 and ZnT1 abundance at the PM. Zinc increased Zip4 levels but reduced Zip4 abundance at the PM. Our results indicate that both PG and Zn regulate Zn transfer across the trophoblast; however, effects are mediated through opposing mechanisms. Thus, PG is implicated in the regulatory mechanisms responsible for Zn transfer to the fetus.