Cadmium down-regulates 11β-HSD2 expression and elevates active glucocorticoid level via PERK/p-eIF2α pathway in placental trophoblasts.

Fetal overexposure to active glucocorticoid (GC) is the major cause for fetal growth restriction (FGR). This study investigated the influences of cadmium (Cd) exposure on active GC and its mechanism in placental trophoblasts. Pregnant mice were exposed to CdCl2 (4.5 mg/kg, i.p.). Human JEG-3 cells were treated with CdCl2 (0-20 μM). Prenatal Cd exposure significantly increased active GC level in amniotic fluid and placenta. Similarly, Cd treatment also elevated active GC level in medium. Expectedly, the expression of 11β-HSD2 protein was markedly downregulated in Cd-exposed placental trophoblasts. We further found that Cd activated the PERK/p-eIF2α signaling pathway in placental trophoblasts. Mechanistically, PERK siRNA pretreatment completely blocked PERK/p-eIF2α signaling, and thereby restoring Cd-downregulated 11β-HSD2 protein expression in human placental trophoblasts. We further found that N-acetylcysteine, a well-known antioxidant, obviously reversed Cd-downregulated 11β-HSD2 protein expression by inhibiting p-PERK/p-eIF2α signaling in placental trophoblasts. Overall, our data suggest that Cd activates the PERK/p-eIF2α signaling, down-regulates the protein expression of 11β-HSD2, and thereby elevating active GC level in placental trophoblast.