Placental vitamin D metabolism and its associations with circulating vitamin D metabolites in pregnant women

Background: Little is known about placental vitamin D metabolism and its impact on maternal circulating vitamin D concentrations in humans. Objective: This study sought to advance the current understanding of placental vitamin D metabolism and its role in modulating maternal circulating vitamin D metabolites during pregnancy. Design: Nested within a feeding study, 24 healthy pregnant women (26-29 wk of gestation) consumed a single amount of vitamin D (511 IU/d from diet and a cholecalciferol supplement) for 10 wk. Concentrations of placental and blood vitamin D metabolites and placental messenger RNA (mRNA) abundance of vitamin D metabolic pathway components were quantified. In addition, cultured human trophoblasts were incubated with C-13-cholecalciferol to examine the intracellular generation and secretion of vitamin D metabolites along with the regulation of target genes. Results: In placental tissue, 25-hydroxyvitamin D-3 [25(OH)D-3] was strongly correlated (r = 0.83, P < 0.001) with 24,25-dihydroxyvitamin D-3. Moreover, these placental metabolites were strongly correlated (r <= 0.85, P <= 0.04) with their respective metabolites in maternal circulation. Positive associations (P <= 0.045) were also observed between placental mRNA abundance of vitamin D metabolic components and circulating vitamin D metabolites [i.e., LDL-related protein 2 (LRP2, also known as megalin) with 25(OH)D-3 and the C3 epimer of 25(OH)D-3 [3-epi-25(OH)D-3]; cubilin (CUBN) with 25(OH)D-3; 25-hydroxylase (CYP2R1) with 3-epi-25(OH)D-3; 24-hydroxylase (CYP24A1) with 25(OH)D-3, 3-epi-25(OH)D-3, and 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3]; and 1 alpha-hydroxylase [(CYP27B1) with 3-epi-25(OH)D-3 and 1,25(OH)(2)D-3]. Notably, in vitro experiments with trophoblasts showed increased production and secretion of 25(OH)D-3 and higher CYP24A1 gene transcript abundance in response to cholecalciferol treatment. Conclusions: The numerous associations of many of the placental biomarkers of vitamin D metabolism with circulating vitamin D metabolites among pregnant women [including a CYP27B1-associated increase in 1,25(OH) 2D3] and the evidence of trophoblast production and secretion of vitamin D metabolites, especially 25(OH) D3, suggest that the placenta may play an active role in modulating the vitamin D metabolite profile in maternal circulation in human pregnancy.