A convergent model for placental dysfunction encompassing combined sub-optimal one-carbon donor and vitamin D bioavailability.

Summary: We hypothesise that the risk of placental dysfunction/insufficiency rises cumulatively in response to several interdependent risk factors that convergently regulate 1,25-dihydroxyvitamin D (the biologically active form of vitamin D, [1,25-(OH)₂D]) levels at the feto-maternal interface. These factors include; (i) disturbances in genetic or epigenetic regulation of one-carbon metabolism and/or vitamin D metabolism and (ii) insufficiency in maternal vitamin D or in dietary intake of micronutrients that are involved in one-carbon donation. We predict that the sub-optimal functioning of folate and vitamin D metabolic pathways, in concert, represents a potential novel risk pathway for adverse pregnancy outcomes. We base this prediction on five observations: [(i)] evidence linking polymorphisms in genes regulating one-carbon donor production and vitamin D metabolism with adverse pregnancy outcomes involving placental dysfunction; [(ii)] evidence linking sub-optimal maternal levels of both one-carbon donor and 1,25-(OH)₂D precursors to adverse pregnancy outcomes involving placental dysfunction; [(iii)] the requirement for adequate one-carbon donor molecules (produced solely from dietary sources) to establish epigenetic markings involving DNA methylation, in the developing placenta and fetus; [(iv)] the demonstrated modulation of vitamin D pathway regulatory genes by DNA methylation; and [(v)] data demonstrating specific DNA methylation-induced epigenetic silencing of the 24-hydroxylase gene (CYP24A1), encoding the major catabolic enzyme of 1,25-(OH)₂D, and 25-hydroxyvitamin D (25-(OH)₂D) in the placenta. It is anticipated that this ‘uncouples’ vitamin D homeostasis at the feto-maternal interface, allowing accumulation of the higher levels of 1,25-(OH)₂D seen in pregnancy. In order to test this model, future epidemiological studies aimed at identifying risk factors for disorders linked to sub-optimal placental development and functioning, should: (a) measure circulating precursor molecules (including folate, vitamin B12, homocysteine, and vitamin D) in maternal and cord blood; (b) collect samples for examination of genotypic variation in both one-carbon and vitamin D regulatory genes and, (c) collect samples for examination of epigenetic status of genes regulating vitamin D homeostasis and action in the placenta. [Copyright &y& Elsevier]