Placental inflammation is associated with brain damage in the neonate highlighting the placental-brain-axis

• In Event: New insights into the role of environmental factors in the development of individuals born preterm

Abstract

While cerebral white matter (WM) is the most common anatomic location of neonatal brain injury among children born extremely prematurely (<28 weeks’ gestation), factors that predispose newborns to WM damage remain understudied. In relation to studies of the placenta-brain axis, dysregulated placental gene expression may play a role in preterm brain damage given its implication in programming early life origins of disease, including neurological disorders. We hypothesized that transcripts that encode proteins that are involved in proinflammatory processes would be highly expressed in the placentas of children who developed ultrasound-defined indicators of white matter damage. In a cohort of extremely low gestational age newborns (ELGAN), we aimed to investigate the relationship between the placental transcriptome and WM damage as assessed by neonatal cranial ultrasound studies (echolucency and/or ventriculomegaly).
From the originally enrolled cohort born extremely preterm (23 to 27 weeks’ gestation), we examined a sub-cohort of 279 mother-infant dyads with at least two neonatal cranial ultrasounds, demographic data, and placental molecular data. We analyzed the relationship between placental transcriptional profiles and neonatal brain damage adjusting for key covariates (Figure 1).

Relative to WM damage, 659 placental genes displayed altered transcriptional profiles. Of these WM damage-associated genes, 244 were dysregulated in the placenta relative to both echolucency and ventriculomegaly. Similar patterns of gene expression were identified for all of the 244 genes identified to be dysregulated in the placenta relative to both echolucency and ventriculomegaly. For this common set of WM damage-related genes, differential expression was observed within critical biological pathways including Interleukin-6, eukaryotic translation initiation factor 2, mammalian target of rapamycin, and pathways highlighting roles for inflammation, apoptosis, and immune response.

In conclusion, differential mRNA expression in the placenta is associated with WM damage in neonates born preterm. These data highlight differential mRNA expression patterning in the placenta and provide insight into potential etiologic factors that may predispose preterm newborns to WM damage. Figure 2 shows associations of the expression of genes involved in the eIF2, mTOR, and IL-6 signaling pathways within the placenta as putative drivers of neurodevelopment later in life. These pathways are broadly tied to apoptosis, inflammation and immune response and their dysregulation in the placenta in infants with WM damage is intriguing. In the ELGAN study, the presence of either echolucency or ventricular enlargement was associated with subsequent development of cerebral palsy,(Kuban et al., 2009) epilepsy,(Campbell et al., 2021) and cognitive impairment(Campbell et al., 2021) and were the ultrasound lesions most predictive of neurodevelopmental impairments. Given that cranial neonatal ultrasound identifies only macroscopic WM damage, in future studies we will conduct additional analyses using MRI data. Additionally, the analysis of proteomic data could increase understanding of the relationship between molecular processes in the placenta and brain function later in life. These data are among the first to highlight the expression of these critical pathways in placentas collected from infants born extremely prematurely who subsequently developed white matter damage. Future research will explore other perinatal environmental factors as they relate to neonatal inflammation and brain volume.

Authors

• Carmen Amelia Marable, University of North Carolina at Chapel Hill
  Presenting Author

• Kyle Roell

• Karl Kuban

• T. Michael O'Shea, University of North Carolina School of Medicine

• Rebecca Fry