@article{54ab9dc8ec3a4c13962cb5168150c26d,
title = "Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit",
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)D3 by endocytosis, 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 maternal and fetal 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 simply 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. 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.",
keywords = "Calcifediol/metabolism, Female, Fetus/metabolism, Humans, Placenta/metabolism, Pregnancy, Vitamin D/metabolism, Vitamins/metabolism",
author = "Brogan Ashley and Claire Simner and Antigoni Manousopoulou and Carl Jenkinson and Felicity Hey and Frost, {Jennifer M} and Rezwan, {Faisal I} and White, {Cory H} and Lofthouse, {Emma M} and Emily Hyde and Cooke, {Laura D F} and Sheila Barton and Pamela Mahon and Curtis, {Elizabeth M} and Moon, {Rebecca J} and Crozier, {Sarah R} and Inskip, {Hazel M} and Godfrey, {Keith M} and Holloway, {John W} and Cyrus Cooper and Jones, {Kerry S} and Lewis, {Rohan M} and Martin Hewison and Garbis, {Spiros D D} and Branco, {Miguel R} and Harvey, {Nicholas C} and Cleal, {Jane K}",
note = "Funding Information: This project has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement InvADeRS no. 841172 to JMF. Funding Information: 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 partner-ship 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 Sk?odowska-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. Funding Information: 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). Funding Information: 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{\textquoteright}s Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition, under grant agreement 289346 and the European Union{\textquoteright}s Horizon 2020 research and innovation program (LIFECYCLE, grant agreement no. 733206). Funding Information: 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). Funding Information: EC has been supported by the Wellcome Trust (201268/Z/16/Z) and an NIHR Clinical Lectureship. Funding Information: CS was funded by a Gerald Kerkut Charitable Trust studentship and BA by Rank Prize and University of Southampton Vice Chancellor{\textquoteright}s Studentships plus the MRC. Funding Information: 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. Funding Information: Antigoni Manousopoulou: AM is CSO of Proteas Bioanalytics Inc, BioLabs at the Lundquist Institute. Cory H White: Cory H White is affiliated with Merck Exploratory Science Centre, Merck Research Laboratories. The author has no financial interests to declare. Elizabeth M Curtis: EC reports honoraria/ travel support from Eli Lilly, UCB, Pfizer and Amgen outside the submitted work. Martin Hewison: MH has received an honorarium for presenting to Thornton and Ross. Spiros DD Garbis: SG is President and CEO/CTO of Proteas Bioanalytics Inc, BioLabs at the Lundquist Institute. Nicholas C Harvey: NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, UCB, Consilient Healthcare, Kyowa Kirin and Internis Pharma, outside the submitted work. The other authors declare that no competing interests exist. Funding Information: 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. Publisher Copyright: {\textcopyright} Ashley et al.",
year = "2022",
month = mar,
day = "8",
doi = "10.7554/eLife.71094",
language = "English",
volume = "11",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications Ltd",
}
