The association of antioxidant-related metabolites with infant neurocognition at two-year-olds
Our study suggests that the downregulation of antioxidants associated metabolic pathways, including cysteine, methionine and glutathione metabolism are correlated with the impaired infant neurodevelopment in the problem-solving domain (Figure 4C ). Cysteine is a vital sulfur-containing amino acid that acts as a precursor for the biosynthesis of glutathione and acetyl-CoA.18 A cysteine-hub metabolic network has been reported to regulate oxidative stress, energy metabolism, and cellular autophagy.19Accumulating evidence has indicated that lower cysteine levels may trigger vascular endothelium damage in maternal-placenta-fetal circulation through oxidative stress in FGR.10,20-23Our previous publications showed that the metabolic profiles of the umbilical cord, neonatal hair, and meconium were consistently characterized by reduced methionine and cysteine levels in twins with selective FGR.11,12,14 Emerging studies suggest that H2S, produced from L-cysteine by cystathionine-β-synthase within the brain, reduces oxidative stress-induced injury and protects against cognitive dysfunction resulting from neuroinflammation.24 L-cysteine administration significantly suppresses hypoxia-ischemia (HI)-induced neuroinflammation in neonatal mice by releasing H2S.25 In addition, low levels of methionine and cysteine may interfere with one-carbon metabolism and inhibit DNA synthesis and methylation, which may subsequently impede embryonic and fetal growth.26
Glutathione (GSH), comprising glutamic acid, cysteine, and glycine, is one of the most important antioxidants in the central nervous system.27,28 Authors suggested that the enhanced GSH to limit oxidative stress could ameliorate neuronal injury and improve motor and cognitive function in mice.29 Neurons are particularly vulnerable to oxidative stress, given that neuronal survival is dependent on the glutathione redox potential.30 Animal models of FGR have shown oxidative stress and mitochondrial dysfunction in the brain31with decreased concentrations of GSH in various cerebral cortex regions, including the temporoparietal, frontal, and occipital lobes after 90 minutes of hypoxia.32 This suggested that the cortex may be more vulnerable to injury due to oxidative stress than other regions and this may have long-term neurodevelopmental implications.
As the product of cysteine, acetyl CoA is the substrate of the TCA cycle and lower levels are related to the imbalance of redox homeostasis in mitochondria. Mews et al found that acetyl coenzyme A synthetase 2 (ACSS2), an enzyme responsible for producing acetyl coenzyme A, can directly regulate histone acetylation (an epigenetic mark) in mammalian neurons and the expression of genes related to cognition and memory, thus affecting spatial memory.33 Recent study demonstrated that ACSS2 is a critical regulator of fear-memory formation in mice and in rats.34 Based on these findings, we speculated that intrauterine cysteine levels and related metabolic pathways identified here may play a role in the neurocognitive development of DCDA-D twins.