Neurodevelopmental Outcomes of Prenatal Preeclampsia Exposure

Gumusoglu, Serena B.; Chilukuri, Akanksha Sri Satya; Santillan, Donna A.; Santillan, Mark K.; Stevens, Hanna E.

doi:10.1016/j.tins.2020.02.003

Cited by 113 publications

(80 citation statements)

References 123 publications

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“…Given the large and growing body of research evidencing a risk of preeclampsia to neurodevelopment, it is critical that mechanisms and physiology underlying this risk are studied in animal models 3 . In the present study, we determined that a chronic AVP infusion mouse model, validated for its relevance to preeclampsia 14 , 15 , resulted in altered offspring neurobiology and behavior.…”

Section: Discussionmentioning

confidence: 99%

Altered offspring neurodevelopment in an arginine vasopressin preeclampsia model

et al. 2021

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Preeclampsia is a severe gestational hypertensive condition linked to child neuropsychiatric disorders, although underlying mechanisms are unclear. We used a recently developed, clinically relevant animal model of preeclampsia to assess offspring. C57BL/6J mouse dams were chronically infused with arginine vasopressin (AVP) or saline (24 ng/h) throughout pregnancy. Adult offspring were behaviorally tested (Y-maze, open field, rotarod, social approach, and elevated plus maze). Offspring brain was assessed histologically and by RNA sequencing. Preeclampsia-exposed adult males exhibited increased anxiety-like behavior and social approach while adult females exhibited impaired procedural learning. Adult AVP-exposed males had reduced total neocortical volume. Adult AVP-exposed females had increased caudate–putamen volume, increased caudate–putamen cell number, and decreased excitatory synapse density in hippocampal dentate gyrus (DG), CA1, and CA3. At postnatal day 7 (P7), AVP-exposed male and female offspring both had smaller neocortex. At P7, AVP-exposed males also had smaller caudate–putamen volume, while females had increased caudate–putamen volume relative to neocortical size. Similar to P7, E18 AVP-exposed offspring had smaller dorsal forebrain, mainly in reduced intermediate, subventricular, and ventricular zone volume, particularly in males. Decreased volume was not accounted for by cell size or cerebrovascular vessel diameter changes. E18 cortical RNAseq revealed 49 differentially-expressed genes in male AVP-exposed offspring, over-representing cytoplasmic translation processes. In females, 31 genes were differentially-expressed, over-representing collagen-related and epithelial regulation pathways. Gene expression changes in E18 AVP-exposed placenta indicated potential underlying mechanisms. Deficits in behavior and forebrain development in this AVP-based preeclampsia model were distinctly different in males and females, implicating different neurobiological bases.

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Section: Discussionmentioning

confidence: 99%

Altered offspring neurodevelopment in an arginine vasopressin preeclampsia model

et al. 2021

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“…Not only did our cell-type-specific differential expression analysis show that the differentially expressed genes we detected in the bulk placenta were minimally affected by cell-type heterogeneity, we detected genes whose celltype-specific expression has large associations with IQ and SRS. For instance, we detected a syncytiotrophoblastspecific association between IQ and ATP2B1, a gene that has been implicated in preeclampsia [66,67], an in utero condition that is partially mediated by dysfunctional syncytiotrophoblasts [99] and has negative impacts with childhood neurodevelopment [100,101]. In addition, ATP2B1 encodes PMCA1, a plasma membrane calcium ion pump, shown to have reduced activity in fetal-facing syncytiotrophoblast basal plasma membranes in patients with preeclampsia compared to controls [102][103][104][105].…”

Section: Discussionmentioning

confidence: 97%

Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm

Santos¹,

Bhattacharya

Joseph

et al. 2020

Molecular Autism

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Background Children born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes. Methods We examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS. Results Genes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case–control status. Limitations The ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited. Conclusions Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.

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“…Epidemiological studies link maternal stress with offspring neurodevelopmental impairments ( 2 ), and animal studies have demonstrated causality of this relationship. For example, preeclampsia—a disorder with disrupted maternal vascular and immune biology—increases risk of neuropsychiatric problems among children ( 3 ). Evidence has come from human and non-human preeclampsia studies implicating what in the offspring brain has changed: its morphology, white matter, and vasculature.…”

Section: Introductionmentioning

confidence: 99%