Sp1 participates in the cadmium-induced imbalance of the placental glucocorticoid barrier by suppressing 11β-HSD2 expression

Cadmium (Cd) is widely present in the environment as a heavy metal poison. Prenatal Cd exposure can damage the placental glucocorticoid barrier, leading to foetal growth restriction (FGR), but the molecular mechanism is unknown. We aimed to study the effects of prenatal Cd exposure on 11 beta-HSD2 and its possible involvement in Cd induced damage in the placental glucocorticoid barrier. Pregnant rats were treated with CdCl2 (1.0 mg/kg/day) by gavage from gestational day (GD) 9-19. Maternal exposure to Cd increased the FGR rate of the offspring, and the levels of corticosterone in the placenta, maternal and foetal serum. Further in vitro experiments with placenta or JEG3 cells indicated that Cd was able to decrease 11 beta-HSD2 and Sp1 expression in trophoblast cells but did not affect 11 beta-HSD1. Additionally, decreased p300 and SP1 enrichment at the 11 beta-HSD2 promoter region was observed in the cells treated with Cd. Decreasing or increasing Sp1 expression accordingly inhibited or promoted the expression of 11 beta-HSD2 and further decreased or increased p300 and Sp1 enrichment at the 11 beta-HSD2 promoter region. In conclusion, Cd inhibits the expression of 11 beta-HSD2 by affecting the binding of p300 to 11 beta-HSD2 via a decrease in Sp1 expression, which damages the placental glucocorticoid barrier and exposes the foetus to excessive glucocorticoids, resulting in FGR. These findings reveal a possible underlying molecular mechanism by which Cd exposure leads to FGR. (C) 2020 Published by Elsevier Ltd.