Investigating a suitable model for the study of vitamin D mediated regulation of human placental gene expression

Simner, Claire; Ashley, Brogan; Cooper, Cyrus; Harvey, Nicholas C.; Lewis, Rohan M.; Cleal, Jane K.

doi:10.1016/j.jsbmb.2019.105576

Cited by 12 publications

(15 citation statements)

References 16 publications

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“…The primary barrier to transfer, the placental syncytiotrophoblast, expresses the vitamin D-metabolizing enzymes 24-hydroxylase ( CYP24A1 ) and 1α-hydroxylase ( CYP27B1 ) ( Simner et al, 2020 ). There was direct evidence of 24-hydroxylase action in the placental tissue with metabolism of 25(OH)D 3 into 13 C-24,25(OH) 2 D 3 ( Figure 1c and d ) but no detectable epi25(OH)D 3.…”

Section: Resultsmentioning

confidence: 99%

“…In the kidney, both DBP and albumin bind to the plasma membrane receptors megalin (LDL-related protein 2 [ LRP2 ]) and cubilin ( CUBN ) ( Birn et al, 2000 ; Doherty and McMahon, 2009 ), which mediate vitamin D internalization by clathrin-dependent endocytosis ( Nykjaer et al, 1999 ; Nykjaer et al, 2001 ). Both receptors are expressed in the primary barrier to transfer the syncytiotrophoblast, suggesting a role for vitamin D uptake by the placenta ( Simner et al, 2020 ). To investigate this, fresh placental villous fragments (n = 4–5 placentas per treatment) were incubated with 20 µM 25(OH)D 3 and albumin, plus the endocytic inhibitors 5 mM amiloride, 10 µM cytochalasin D, and 2 µM receptor-associated protein (RAP), which block pinocytosis, classical clathrin-dependent endocytosis, and megalin-mediated endocytosis (one type of clathrin-dependent endocytosis), respectively.…”

Section: Resultsmentioning

confidence: 99%

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

Ashley

Simner

Manousopoulou

et al. 2022

eLife

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Ashley

Simner

Manousopoulou

et al. 2022

eLife

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“…The primary barrier to transfer, the placental syncytiotrophoblast, expresses the vitamin D-metabolising enzymes 24-hydroxylase ( CYP24A1 ) and 1α-hydroxylase ( CYP27B1 ) [26]. There was direct evidence of 24-hydroxylase action in the placental tissue with metabolism of 25(OH)D 3 into 13 C-24,25(OH) 2 D 3 (Figure 1c & 1d) but no detectable epi25(OH)D 3 Placental 13 C-25(OH)D 3 and 13 C-24,25(OH) 2 D levels were positively correlated (r = 0.998, p = 0.0001; Figure 1g).…”

Section: Resultsmentioning

confidence: 99%

“…In the kidney, both DBP and albumin bind to the plasma membrane receptors megalin (LDL-related protein 2 ( LRP2 )) and cubilin ( CUBN ) [29, 30], which mediate vitamin D internalisation by clathrin-dependant endocytosis [25, 31]. Both receptors are expressed in the primary barrier to transfer, the syncytiotrophoblast, suggesting a role for vitamin D uptake by the placenta [26]. To investigate this, fresh placental villous fragments (n = 4-5 placentas per treatment) were incubated with 20 μM 25(OH)D 3 and albumin, plus the endocytic inhibitors 5 mM amiloride, 10 μM cytochalasin D and 2 μM Receptor Associated Protein (RAP) which block pinocytosis, classical clathrin-dependent endocytosis and megalin-mediated endocytosis, respectively.…”

Section: Resultsmentioning

confidence: 99%

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

Ashley¹,

Simner²,

Manousopoulou³

et al. 2021

Preprint

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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.

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“…Ligand-activated VDR binds to accessible genomic sites in the vicinity of its target genes and modulates their transcription, with possible multi-organ consequences. It is thus now accepted that vitamin D plays a role in many organs, especially in the placenta 8 , through the regulation of the expression of key associated-developmental genes [9][10][11] . The 1,25(OH)D concentrations in the maternal systemic circulation and the placenta increase during pregnancy.…”

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confidence: 99%

Vitamin D deficiency during late pregnancy mediates placenta-associated complications

Raia-Barjat

Sarkis

Rançon

et al. 2021

Sci Rep

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During pregnancy, maternal vitamin D insufficiency could increase the risk of preeclampsia. Aim of the study was to evaluate the relationship between vitamin D status and the occurrence of placenta-mediated complications (PMCs) in a population at high risk. A prospective multicenter cohort study of 200 pregnant patients was conducted. The vitamin D level of patients with placenta-mediated complications was lower at 32 weeks compared to uncomplicated pregnancies (P = 0.001). At 32 weeks, the risk of occurrence of PMCs was five times higher in patients with vitamin D deficiency (RR: 5.14 95% CI (1.50–17.55)) compared to patients with normal vitamin D levels. There was a strong, inverse relationship between serum 25(OH)D levels at 32 weeks and the subsequent risk of PMCs (P = 0.001). At 32 weeks, the vitamin D level of patients with late-onset PMCs was lower than the one of patients with early-onset PMCs and of patients without PMCs (P < 0.0001). These results suggest a role of vitamin D in the maintenance of placental performance and therefore in the prevention of the onset of late PMC.

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Investigating a suitable model for the study of vitamin D mediated regulation of human placental gene expression

Cited by 12 publications

References 16 publications

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

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

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

Vitamin D deficiency during late pregnancy mediates placenta-associated complications

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