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.