Date Published: March 7, 2018
Publisher: Public Library of Science
Author(s): Sloane K. Tilley, Elizabeth M. Martin, Lisa Smeester, Robert M. Joseph, Karl C. K. Kuban, Tim C. Heeren, Olaf U. Dammann, T. Michael O’Shea, Rebecca C. Fry, Gijs B Afink.
The placenta is the central regulator of maternal and fetal interactions. Perturbations of placental structure and function have been associated with adverse neurodevelopmental outcomes later in life. Placental CpG methylation represents an epigenetic modification with the potential to impact placental function, fetal development and child health later in life.
Genome-wide placental CpG methylation levels were compared between spontaneous versus indicated deliveries from extremely preterm births (EPTBs) (n = 84). The association between the identified differentially methylated CpG sites and neurocognitive outcome at ten years of age was then evaluated.
Spontaneous EPTB was associated with differential CpG methylation levels in 250 CpG sites (217 unique genes) with the majority displaying hypermethylation. The identified genes are known to play a role in neurodevelopment and are enriched for basic helix-loop-helix transcription factor binding sites. The placental CpG methylation levels for 17 of these sites predicted cognitive function at ten years of age.
A hypermethylation signature is present in DNA from placentas in infants with spontaneous EPTB. CpG methylation levels of critical neurodevelopment genes in the placenta predicted later life cognitive function, supporting the developmental origins of health and disease hypothesis (DOHaD).
Preterm infants have an increased risk of cognitive impairment later in life . In the Extremely Low for Gestational Age Newborns (ELGAN) cohort, indicators and antecedents of perinatal inflammation are associated with a range of neurodevelopmental outcomes in early and later childhood, including mental and motor impairment, behavioral problems, and cerebral palsy [2–6]. As the placenta mediates maternal-fetal interactions, it is likely that placental signaling is involved in these adverse developmental outcomes .
Infants born prematurely have a higher risk of later-life cognitive impairments than those born at term, and the severity of these adverse outcomes is inversely associated with gestational age . Intrauterine inflammation and its antecedents are associated with both premature birth and preterm infants’ risk of later-life cognitive impairments . Although the exact mechanism by which inflammation alters neurodevelopment is unknown, the current literature postulates that placental epigenetics may be an important determinant of changes in early-life neurodevelopmental programming in response to inflammation [7, 11]. For example, DNA methylation levels of the glucocorticoid receptor (NR3C1) and 11β-hydroxysteroid dehydrogenase type 2 (HSD11B1), have been associated with adverse newborn neurobehavior [8–10].