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 ¹³C-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 D₃ [25(OH)D₃] was strongly correlated (r = 0.83, P, 0.001) with 24,25-dihydroxyvitamin D₃. 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)D₃ and the C3 epimer of 25(OH)D₃ [3-epi-25(OH)D₃]; cubilin (CUBN) with 25(OH)D₃; 25-hydroxylase (CYP2R1) with 3-epi-25(OH)D₃; 24-hydroxylase (CYP24A1) with 25(OH)D₃, 3-epi-25(OH)D₃, and 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]; and 1a-hydroxylase [(CYP27B1) with 3-epi-25(OH)D₃ and 1,25(OH)₂D₃]. Notably, in vitro experiments with trophoblasts showed increased production and secretion of 25(OH)D₃ 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. This trial was registered at clinicaltrials.gov as NCT03051867.