The Epigenetic Role of Vitamin C in Neurodevelopment

Abstract

The maternal diet during pregnancy is a key determinant of offspring health. Early studies have linked poor maternal nutrition during gestation with a propensity for the development of chronic conditions in offspring. These conditions include cardiovascular disease, type 2 diabetes and even compromised mental health. While multiple factors may contribute to these outcomes, disturbed epigenetic programming during early development is one potential biological mechanism. The epigenome is programmed primarily in utero, and during this time, the developing fetus is highly susceptible to environmental factors such as nutritional insults. During neurodevelopment, epigenetic programming coordinates the formation of primitive central nervous system structures, neurogenesis, and neuroplasticity. Dysregulated epigenetic programming has been implicated in the aetiology of several neurodevelopmental disorders such as Tatton-Brown-Rahman syndrome. Accordingly, there is great interest in determining how maternal nutrient availability in pregnancy might affect the epigenetic status of offspring, and how such influences may present phenotypically. In recent years, a number of epigenetic enzymes that are active during embryonic development have been found to require vitamin C as a cofactor. These enzymes include the ten-eleven translocation methylcytosine dioxygenases (TETs) and the Jumonji C domain-containing histone lysine demethylases that catalyse the oxidative removal of methyl groups on cytosines and histone lysine residues, respectively. These enzymes are integral to epigenetic regulation and have fundamental roles in cellular differentiation, the maintenance of pluripotency and development. The dependence of these enzymes on vitamin C for optimal catalytic activity illustrates a potentially critical contribution of the nutrient during mammalian development. These insights also highlight a potential risk associated with vitamin C insufficiency during pregnancy. The link between vitamin C insufficiency and development is particularly apparent in the context of neurodevelopment and high vitamin C concentrations in the brain are indicative of important functional requirements in this organ. Accordingly, this review considers the evidence for the potential impact of maternal vitamin C status on neurodevelopmental epigenetics.

Ablation of placental REST deregulates fetal brain metabolism and impacts gene expression of the offspring brain at the postnatal and adult stages

“…Vitamin C (vitC) plays a key neuroprotection role in the postnatal brain against glutamateinduced neurodegeneration, and functions as a cofactor of epigenetic enzymes such as ten-eleven translocation methylcytosine dioxygenases (TETs) and the Jumonji C domain-containing histone lysine demethylases to facilitate epigenetic modification of the postnatal brain. 57,[77][78][79] The brain undergoes extensive epigenetic modification during postnatal development. 77 The brain epigenome modification at the postnatal period is required for hypocampal neurogenesis in adult life.…”

“…This suggested that a lack of REST in the placenta induced an adaptive metabolic response of the offspring brain during development from the postnatal to adult life. Important brain metabolites such as vitamin C (ascorbate), lactate, creatine, and glutamate [54][55][56][57][58] were associated with this metabolic response (Table 2). Lactate fuels brain energy, 54 glutamate and creatine help the brain respond to stress conditions, including cerebral hypoxic conditions, 55,56 and ascorbate acts as a co-factor of specific epigenetic enzymes in the brain.…”

Inflammation and Vitamin C in Women with Prenatal Depression and Anxiety: Effect of Multinutrient Supplementation

“…This could be due to a number of factors, such as vomiting, non-compliance, or low bioavailability of the supplement. Vitamin C has important roles to play in epigenetic regulation during development [ 40 ] and is also a cofactor for collagen synthesis, with supplementation showing positive benefits regarding attenuating premature rupture of membranes (RR 0.66, 95% CI 0.48–0.91) [ 41 ]. Low vitamin C status has also been associated with higher odds of developing pre-eclampsia (OR 3.8, 95% CI 1.7–8.8) [ 42 ].…”

Ascorbic acid modulates immune responses through Jumonji‐C domain containing histone demethylases and Ten eleven translocation (TET) methylcytosine dioxygenase

“…They assessed the methylation status of H3 histone by western blots and reported that ascorbic acid reversibly reduced the level of H3K36me2/3. [ 104 ] Extended studies showed that ascorbic acid‐mediated H3K36 demethylation was accomplished by JHDM1A/1B [ 104–107 ] X‐ray crystallography revealed that the catalytic site of JHDM family members resides at the N‐terminal JmjN domain. In this domain, a long helix and two short helices were sandwiched between two β‐strands.…”