Placental transcriptional signatures associated with cerebral white matter damage in the neonate

Abstract

Cerebral white matter is the most common anatomic location of neonatal brain injury in preterm newborns. Factors that predispose preterm newborns to white matter damage are 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. There is a critical need to investigate the relationships between the placental transcriptome and white matter damage in the neonate. In a cohort of extremely low gestational age newborns (ELGANs), we aimed to investigate the relationship between the placental transcriptome and white matter damage as assessed by neonatal cranial ultrasound studies (echolucency and/or ventriculomegaly). We hypothesized that genes involved in inflammatory processes would be more highly expressed in placentas of ELGANs who developed ultrasound-defined indicators of white matter damage. Relative to either form of white matter damage, 659 placental genes displayed altered transcriptional profiles. Of these white matter damage-associated genes, largely distinct patterns of gene expression were observed in the study (n = 415/659 genes). Specifically, 381 genes were unique to echolucency and 34 genes were unique to ventriculomegaly. Pathways involved in hormone disruption and metabolism were identified among the unique echolucency or ventriculomegaly genes. Interestingly, a common set of 244 genes or 37% of all genes was similarly dysregulated in the placenta relative to both echolucency and ventriculomegaly. For this common set of white matter damage-related genes, pathways involved in inflammation, immune response and apoptosis, were enriched. Among the white matter damage-associated genes are genes known to be involved in Autism Spectrum Disorder (ASD) and endocrine system disorders. These data highlight differential mRNA expression patterning in the placenta and provide insight into potential etiologic factors that may predispose preterm newborns to white matter damage. Future studies will build upon this work to include functional measures of neurodevelopment as well as measures of brain volume later in life.

A multi‐omic approach identifies an autism spectrum disorder (ASD) regulatory complex of functional epimutations in placentas from children born preterm

“…Further, impaired UPF2 function has been associated with neurodevelopmental dysfunction by activating the immune response (Johnson et al, 2019). Highlighting the potential relationship of the altered expression of these genes in the placenta and brain damage in the ELGAN neonate, four of the ASD predictors were also associated with cerebral white matter damage in neonates, namely, BAZ2A , MT‐CO3 , Bromodomain Containing 7 ( BRD7) and Phosphoglucomutase 5 Pseudogene 2 ( PGM5P2 ) (Marable et al, 2022).…”

“…Abnormal placental function during pregnancy is tied to adverse later‐life outcomes in the offspring including heart disease, obesity, and impaired neurodevelopment (Barker et al, 1990; Bronson & Bale, 2016). In particular, alterations in the placental transcriptome have been linked to brain damage and to the development of adverse neurodevelopmental outcomes (Bangma et al, 2021; Freedman et al, 2022; Marable et al, 2022; Oldenburg et al, 2021) supporting the placenta‐brain‐axis. Still, the role of the placental epigenome in regulating these transcriptome‐level changes is not well established.…”

Accelerated Aging and the Life Course of Individuals Born Preterm

“…Preterm birth [78,79] and cerebrovascular disease [80,81] are associated with systemic inflammation. In the ELGAN cohort, neonatal systemic inflammation was associated with increased risks of cerebral palsy, learning and development deficiencies, and reduced white and grey matter volumes in the brain [82][83][84][85]. Fetuses with biomarkers of placental inflammation were more likely to exhibit neonatal systemic inflammation.…”

Prenatal Alcohol Exposure Impairs the Placenta–Cortex Transcriptomic Signature, Leading to Dysregulation of Angiogenic Pathways

“…Interestingly, Igf1 was one of the ligands which appeared to be dysregulated by PAE in the present placenta-cortex signature. In relation to neuroplacentology, a recent clinical study aimed to establish a transcriptomic placental signature of neonates who developed cerebral white matter damage [44]. The results showed that in the group of infants with white matter lesions, several processes such as inflammation were dysregulated in the placenta [44].…”

“…In relation to neuroplacentology, a recent clinical study aimed to establish a transcriptomic placental signature of neonates who developed cerebral white matter damage [44]. The results showed that in the group of infants with white matter lesions, several processes such as inflammation were dysregulated in the placenta [44]. However, due to the difficulty of obtaining brain tissues from human neonates, such clinical studies fail to demonstrate functional/mechanistic links.…”