Preterm Birth and the Risk of Neurodevelopmental Disorders - Is There a Role for Epigenetic Dysregulation?

Abstract

Preterm Birth (PTB) accounts for approximately 11% of all births worldwide each year and is a profound physiological stressor in early life. The burden of neuropsychiatric and developmental impairment is high, with severity and prevalence correlated with gestational age at delivery. PTB is a major risk factor for the development of cerebral palsy, lower educational attainment and deficits in cognitive functioning, and individuals born preterm have higher rates of schizophrenia, autistic spectrum disorder and attention deficit/hyperactivity disorder. Factors such as gestational age at birth, systemic inflammation, respiratory morbidity, sub-optimal nutrition, and genetic vulnerability are associated with poor outcome after preterm birth, but the mechanisms linking these factors to adverse long term outcome are poorly understood. One potential mechanism linking PTB with neurodevelopmental effects is changes in the epigenome. Epigenetic processes can be defined as those leading to altered gene expression in the absence of a change in the underlying DNA sequence and include DNA methylation/hydroxymethylation and histone modifications. Such epigenetic modifications may be susceptible to environmental stimuli, and changes may persist long after the stimulus has ceased, providing a mechanism to explain the long-term consequences of acute exposures in early life. Many factors such as inflammation, fluctuating oxygenation and excitotoxicity which are known factors in PTB related brain injury, have also been implicated in epigenetic dysfunction. In this review, we will discuss the potential role of epigenetic dysregulation in mediating the effects of PTB on neurodevelopmental outcome, with specific emphasis on DNA methylation and the α-ketoglutarate dependent dioxygenase family of enzymes.

Keywords: DNA methylation; Epigenetic; Epigenetic dysregulation; Neurodevelopmental disorders; Preterm birth; α-ketoglutarate dependent dioxygenase.

Fig. (1)

During PTB related insults, glia within the CNS are particularly vulnerable to stressors and mediate many of the pathogenic outcomes associated with PTB. Astrocytes are central to the excitotoxic response, which involves glutamate recycling and its de novo synthesis. Oligodendrocytes and oligodendrocyte precursor cells (OPC) are vulnerable to oxidative stress and other factors associated with hypoxia, inflammation and excitotoxicity as periods critical for their correct maturation and development overlap with the time during which PTB related insults may occur [48, 168] (surface area of an individual OPC’s membrane can increase up to 6,500 fold during these times [169]). The death of OPCs is of particular importance during development as this leads to a shortage of mature oligodendrocytes which may result in aberrant myelination in deep white matter tracts of the brain, leading to impaired signalling and neuronal death, which can be seen pathologically as periventricular leukomalacia, an anatomical feature of cerebral palsy. Microglia can become activated in response to infection in utero or postnatally, this population transition is central to the inflammatory response within the CNS and increased levels of microglial activation can also be seen in post-mortem ASD tissue in the prefrontal cortex of male patients [41].

Fig. (2)

During normoxia the TCA cycle has many reversible reactions with 2 “stop/go” points of irreversible reactions, at the conversion of oxaloacetate to citrate and likewise the conversion of α-ketoglutarate to succinyl CoA. During hypoxia, as the cell needs ATP and NAD+, the TCA metabolite flow predominately proceeds towards succinate production from α-ketoglutarate to account for ATP lost from electron transport failure and oxaloacetate is preferentially converted to malate to increase mitochondrial NAD. This leads to a build-up of fumarate and succinate which are known to inhibit the function of the α-ketoglutarate dependent dioxygenases. It has also been shown that under hypoxic conditions α-ketoglutarate can be converted, primarily by lactate dehydrogenase, to L-hydroxyglutarate, which also can inhibit members of the α-ketoglutarate dependent dioxygenase family. The metabolites which have been shown to either directly promote (α-ketoglutarate) or inhibit (succinate, fumarate and L-hydroxyglutarate) activity of the α-ketoglutarate dependent dioxygenases are highlighted in bold.