Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit
Creators: name: Ashley, Brogan
name: Simner, Claire
name: Manousopoulou, Antigoni
name: Jenkinson, Carl
name: Hey, Felicity
name: Frost, Jennifer M
name: Rezwan, Faisal I
name: White, Cory H
name: Lofthouse, Emma M
name: Hyde, Emily
name: Cooke, Laura DF
name: Barton, Sheila
name: Mahon, Pamela
name: Curtis, Elizabeth M
name: Moon, Rebecca J
name: Crozier, Sarah R
name: Inskip, Hazel M
name: Godfrey, Keith M
name: Holloway, John W
name: Cooper, Cyrus
name: Jones, Kerry
name: Lewis, Rohan M
name: Hewison, Martin
name: Garbis, Spiros DD
name: Branco, Miguel R
name: Harvey, Nicholas C
name: Cleal, Jane K
Publisher: name: Apollo - University of Cambridge Repository
Year: 2022
Subjects: Research Article
Developmental Biology
placenta
Vitamin D
fetal programming
epigenetics
transcriptomics
Human

description: Funder: Gerald Kerkut Charitable Trust; FundRef: http://dx.doi.org/10.13039/100012166
description: Funder: Rank Prize
description: Funder: NIHR Clinical Lectureship
description: 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<sub>3</sub> by endocytosis, placental metabolism of 25(OH)D<sub>3</sub> into 24,25-dihydroxyvitamin D<sub>3</sub> and active 1,25-dihydroxyvitamin D [1,25(OH)<sub>2</sub>D<sub>3</sub>], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D<sub>3</sub> and synthesis of 1,25(OH)<sub>2</sub>D<sub>3</sub> demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D<sub>3</sub>. We demonstrate that 25(OH)D<sub>3</sub> 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.
description: CS was funded by a Gerald Kerkut Charitable Trust studentship and BA by Rank Prize and University of Southampton Vice Chancellor’s Studentships plus the MRC. KMG was supported by the UK Medical Research Council (MC_UU_12011/4), the National Institute for Health Research (NIHR Senior Investigator [NF-SI-0515-10042], NIHR Southampton 1000DaysPlus Global Nutrition Research Group [17/63/154], and NIHR Southampton Biomedical Research Centre [IS-BRC-1215-20004]), British Heart Foundation (RG/15/17/3174) and the US National Institute on Aging of the National Institutes of Health (Award No. U24AG047867). KSJ was supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (ISBRC-1215-20014). The NIHR Cambridge Biomedical Research Centre is a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Experimental work performed by KSJ and FH at MRC. EWL was supported by Dr Ann Prentice (UK Medical Research Council U105960371). The SWS has been supported by grants from Medical Research Council (MRC) (4050502589 [MRC LEU]), Dunhill Medical Trust, British Heart Foundation, Food Standards Agency, National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, NIHR Oxford Biomedical Research Centre, University of Oxford, and the European Union’s Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition, under grant agreement 289346 and the European Union’s Horizon 2020 research and innovation program (LIFECYCLE, grant agreement no. 733206). EC has been supported by the Wellcome Trust (201268/Z/16/Z) and an NIHR Clinical Lectureship. Work leading to these results was supported by the BBSRC (HDHL-Biomarkers, BB/P028179/1), as part of the ALPHABET project, supported by an award made through the ERA-Net on Biomarkers for Nutrition and Health (ERA HDHL), Horizon 2020 grant agreement number 696295. The proteomic analyses (SDG and AM) were financially supported by the National Institutes of Health (R21AI122389) and the Beckman Institute at the California Institute of Technology. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement InvADeRS no. 841172 to JMF. The electron microscopy image in Figure 2 was produced with help of the Biomedical imaging unit, Faculty of Medicine, University of Southampton.