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

  1. Brogan Ashley
  2. Claire Simner
  3. Antigoni Manousopoulou
  4. Carl Jenkinson
  5. Felicity Hey
  6. Jennifer M Frost
  7. Faisal I Rezwan
  8. Cory H White
  9. Emma M Lofthouse
  10. Emily Hyde
  11. Laura DF Cooke
  12. Sheila Barton
  13. Pamela Mahon
  14. Elizabeth M Curtis
  15. Rebecca J Moon
  16. Sarah R Crozier
  17. Hazel M Inskip
  18. Keith M Godfrey
  19. John W Holloway
  20. Cyrus Cooper
  21. Kerry S Jones
  22. Rohan M Lewis
  23. Martin Hewison
  24. Spiros DD Garbis
  25. Miguel R Branco
  26. Nicholas C Harvey
  27. Jane K Cleal

  • Curated by eLife

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    Evaluation Summary:

    This manuscript uses primary placental units and villous explants to examine the placental metabolism of vitamin D and effects of vitamin D on placental gene expression. The studies demonstrate that the placenta actively transports 25D, such that the fetal levels are dependent on placental function rather than simple diffusion from the maternal circulation. Furthermore, they demonstrate actions of vitamin D on placental gene expression. This paper should be of interest to cell biologists and obstetricians/gynaecologists studying the role of the placenta in fetal growth and development.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Abstract

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D 3 by endocytosis, placental metabolism of 25(OH)D 3 into 24,25-dihydroxyvitamin D 3 and active 1,25-dihydroxyvitamin D [1,25(OH) 2 D 3 ], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D 3 and synthesis of 1,25(OH) 2 D 3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D 3 . We demonstrate that 25(OH)D 3 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. 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 demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.

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  1. Version published to 10.7554/elife.71094 on eLife
  2. eLife

    Evaluation Summary:

    This manuscript uses primary placental units and villous explants to examine the placental metabolism of vitamin D and effects of vitamin D on placental gene expression. The studies demonstrate that the placenta actively transports 25D, such that the fetal levels are dependent on placental function rather than simple diffusion from the maternal circulation. Furthermore, they demonstrate actions of vitamin D on placental gene expression. This paper should be of interest to cell biologists and obstetricians/gynaecologists studying the role of the placenta in fetal growth and development.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  3. eLife

    Reviewer #1 (Public Review):

    The premise for this manuscript is that vitamin D is important for optimal fetal development. The data for this is correlative and there are human and murine mutations in the vitamin D receptor that do not show important abnormalities in the affected fetuses. However, this does not diminish the important findings of active transport of vitamin D metabolites by the placenta and of significant regulation of target genes in the placenta itself. In the system used, most of the 25D is metabolized by the placenta and only ~10% is transferred to the fetal circulation, which raises questions as to how well this model recapitulates the in vivo dynamics. Of interest, most of the active and inactive metabolites end up in the maternal circulation. This raises the question as to whether there is impaired transport of vitamin D and its metabolites into the fetal circulation in this experimental system. It would have been useful to use a control substance that is readily transported into the fetal circulation to demonstrate that the placental unit is intact. Nevertheless, these studies demonstrate novel findings.

  4. eLife

    Reviewer #2 (Public Review):

    Ashley et al., studied the transfer and metabolism of 25(OH)D3 in maternal and fetal circulations; thereafter utilizing the term human placenta, now considered the "gold standard" among currently available translocation models. Moreover, the authors investigated the effects of vitamin D on placental methylation, transcriptomic, and the proteomic landscape. They demonstrated the active mechanisms of 25(OH)D3 uptake by the placenta and found that placental metabolism of 25(OH)D3 can modify fetal and maternal levels of Vitamin D. Furthermore, the authors have shown that 25(OH) D3 induces placental specific effects on the transcriptome and proteome involving pathways relevant to placental function and fetal development. Moreover, these effects are dependent on the underlying epigenetic landscape.

    This is an important finding because it provides further understanding as to the active role of human placenta in Vitamin D transport and metabolism, with further influence on fetal growth and development.

    Though it is a well-reported descriptive study, transcriptomic and proteomic data require further validation.

  5. Version published to 10.1101/2021.03.01.431439v4 on bioRxiv
  6. Version published to 10.1101/2021.03.01.431439v3 on bioRxiv
  7. Version published to 10.1101/2021.03.01.431439v2 on bioRxiv
  8. Version published to 10.1101/2021.03.01.431439v1 on bioRxiv