Placental uptake and metabolism of 25(OH)Vitamin D determines its activity within the fetoplacental unit

Abstract

Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes, but the underlying mechanisms have not been elucidated. Using physiological human placental perfusion approaches and intact villous explants we demonstrate a role for the placenta in regulating the relationships between maternal 25(OH)D concentrations and fetal physiology. Here, we demonstrate active placental uptake of 25(OH)D3 by endocytosis and placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the fetal and maternal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than solely the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer, including transcriptional activation and inflammatory responses. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta; with widespread effects on the placenta itself. These data show complex and synergistic interplay between vitamin D and the placenta, and inform possible interventions to optimise placental function to better support fetal growth and the maternal adaptations to pregnancy.Significance StatementMaternal 25-hydroxyvitamin D (25(OH)D) is linked to fetal development and subsequent postnatal health, and adverse events in pregnancy, but does not necessarily predict fetal 25(OH)D supply. If, rather than passive diffusion, active placental 25(OH)D uptake and metabolism determine the quantity and type of vitamin D reaching the fetus this becomes a regulated process. Furthermore, 25(OH)D induces placental specific effects on the transcriptome and proteome in patterns relevant to placental function and fetal development, independent of vitamin D transfer. These effects are dependent on the underlying epigenetic landscape. Therefore, maternal 25(OH)D concentrations alone are not sufficient to predict fetal outcome: the synergistic interplay between the placenta and maternal vitamin D becomes critical to ensuring the fetus receives optimal exposure to vitamin D during intrauterine life.

Maternal and Fetal Genetic Variation in Vitamin D Metabolism and Umbilical Cord Blood 25-Hydroxyvitamin D

“…It is often debated whether total 25(OH)D or the free hormone (fraction not bound to DBP or albumin) is important to clinical outcomes (25). However, the association of the rs2282679 genotype observed in our study, and other SNPs in the GC gene identified through GWAS (12) DBP is also present within placental tissue (27) and our recent data suggest that that the interaction of 25(OH)D bound to DBP with megalin/cubilin in the placenta might facilitate uptake of vitamin D into the placenta and its transfer to the fetal circulation (16). Furthermore, maternal plasma DBP levels correlate more strongly with placental gene expression than maternal vitamin D (28).…”

Endocytosis in the placenta: An undervalued mediator of placental transfer

“…As these receptors are expressed at the placental syncytiotrophoblast they may mediate vitamin D uptake in the placenta [15]. The use of pharmacological inhibitors in ex vivo placental explants has provided some evidence that vitamin D uptake into the placenta is mediated by endocytosis [43]. Further research is required to establish the precise molecular mechanism(s) responsible.…”