Gestational Vitamin D Supplementation Leads to Reduced Perinatal RXRA DNA Methylation: Results From the MAVIDOS Trial

Abstract

We have previously demonstrated inverse associations between maternal 25(OH)‐vitamin D status and perinatal DNA methylation at the retinoid‐X‐receptor‐alpha (RXRA) locus and between RXRA methylation and offspring bone mass. In this study, we used an existing randomized trial to test the hypothesis that maternal gestational vitamin D supplementation would lead to reduced perinatal RXRA locus DNA methylation. The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicenter, double‐blind, randomized, placebo‐controlled trial of 1000 IU/day cholecalciferol or matched placebo from 14 weeks’ gestation until delivery. Umbilical cord (fetal) tissue was collected at birth and frozen at −80°C ( n = 453). Pyrosequencing was used to undertake DNA methylation analysis at 10 CpG sites within the RXRA locus (identified previously). T tests were used to assess differences between treatment groups in methylation at the three most representative CpG sites. Overall, methylation levels were significantly lower in the umbilical cord from offspring of cholecalciferol‐supplemented mothers, reaching statistical significance at four CpG sites, represented by CpG5: mean difference in % methylation between the supplemented and placebo groups was −1.98% (95% CI, −3.65 to −0.32, p = 0.02). ENCODE (Encyclopedia of DNA Elements) evidence supports the functionality of this locus with strong DNase hypersensitivity and enhancer chromatin within biologically relevant cell types including osteoblasts. Enrichment of the enhancer‐related H3K4me1 histone mark is also seen in this region, as are binding sites for a range of transcription factors with roles in cell proliferation, response to stress, and growth factors. Our findings are consistent with previous observational results and provide new evidence that maternal gestational supplementation with cholecalciferol leads to altered perinatal epigenetic marking, informing mechanistic understanding of early life mechanisms related to maternal vitamin D status, epigenetic marks, and bone development. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Dietary Inflammatory Index and Non-Communicable Disease Risk: A Narrative Review

“…It is possible that nutrients and dietary inflammation may have a direct effect on bone mineralization, for example, maternal pregnancy 25-hydroxyvitamin D concentration is associated with umbilical cord venous serum calcium concentration; expression of a calcium transporter in the placenta is positively associated with neonatal bone mass [289]. However, there is increasing evidence for indirect mechanisms, involving epigenetic signaling, for example perinatal methylation at the retinoid X receptor alpha locus (a key part of vitamin D signalling) is reduced by maternal gestational vitamin D supplementation, and is associated with offspring bone mass [290,291]. Future work examining the relationship between early life or childhood dietary inflammation on future bone health could provide important insights.…”

Vitamin D and its Effects on DNA Methylation in Development, Aging, and Disease

“…There was a corresponding increase in RXRA gene expression. The authors of this study speculate that RXRA methylation may act as a surrogate for the action of vitamin D on other tissues following birth, [ 40 ] presumably because the RXR forms part of the signaling complex that is activated by calcitriol binding. Human studies on vitamin D and DNA methylation are summarized in Table 2 .…”

https://researchopenworld.com/endocrine-disruptors-caused-faulty-hormonal-imprinting-focus-on-women/#

“…The developing immune system, the cells of which have steroid (estrogen) hormone receptors is very sensitive to the presence of endocrine disruptors [35]. Faulty imprinting by endocrine disruptors could be responsible for pathological development of bones as well, as for changes in bone mineralization and osteoporotic fractures or other bone problems [37][38][39][40][41].…”