Neurodevelopment and placental omics
Despina D. Briana and Ariadne Malamitsi-Puchner
The incidence of neurodevelopmental and mental disorders has increased worldwide; therefore, there is a great need to understand the underlying biology, as well as to identify biomarkers of these disorders (1). As the developmental origins of adult disease hypothesis was postulated four decades ago by Barker and associates, intrauterine adversity, including maternal psychosocial stress, infection, and metabolic dysfunction, has systematically been recognized as a risk factor of lifetime metabolic and neuropsychiatric disease susceptibility (2,3). Due to rapid growth and plasticity during gestation, the brain is extremely sensitive to the effects of environmental factors that can provide adaptive advantages or lead to long-term vulnerability (4,5). A variety of maternal and intrauterine insults are known to affect fetal neurodevelopment, but the mechanisms underlying how such transient prenatal challenges can lead to persistent postnatal dysfunctions are largely unknown. Growing evidence suggests that perturbations in the maternal environment are conveyed to the fetus by changes in placental function (6). As the placenta resides at the interface between mother and fetus, it is uniquely positioned to modulate interactions within an adverse intrauterine environment (7). By regulating nutrient transport, endocrine function, and immune tolerance, the placenta is highly implicated in fetal growth restriction (FGR), hypoxia, intrauterine inflammation, and the related neurological complications (8,9). Early identification of infants at risk for neurodevelopmental disorders is crucial to allow for targeted surveillance, early risk assessment, or preventative interventions to be implemented from birth (10). Studying the molecular characteristics of the placenta at birth by using the “omics” techniques has recently been proposed as a way to assess the intrauterine experience and predict future infant neurodevelopmental outcome (10). This chapter summarizes emerging evidence for the utility of placental omics in the prenatal programming of neurodevelopmental disorders.
Placenta as mediator of adverse intrauterine effects on fetal brain development
Far from being a passive organ, the placenta actively maintains intrauterine homeostasis and orchestrates the sequence and intensity of the complex maternal-fetal interactions (8). Signaling of cytokines, growth factors, and hormones is implicated in the cross-talk between maternal and fetal cells in the local microenvironment of the placenta (8). These interactions are critical for establishing normal placental architecture and delivering sufficient oxygen and nutrients to the fetus (8). Maternal insults that disrupt the fine interplay of signaling networks at the maternal-fetal interface can alter placental capacity and complicate fetal development (11). Altered placental function is associated with brain injury and contributes to the pathogenesis of neurodevelopmental disorders. Several maternal insults, such as infection and malnutrition, increase susceptibility to FGR, and epidemiologically increase the risk for development of schizophrenia, autism, and cerebral palsy in the offspring (12–14). Studies of animal models of intrauterine infection and FGR demonstrate that primary placental insults can lead to prenatal brain damage by inducing a variety of neuropathologies, such as disrupted astrocyte development, microglial activation, white-matter damage, and impaired blood-brain barrier integrity (15). Uteroplacental inflammation may induce the expression of apoptotic markers by Purkinje cells of the fetal ovine cerebellum, leading to Purkinje cell loss (16), which characterizes the autistic brain and is common in other neurodevelopmental disorders, such as psychosis. Clinical studies show worse neurodevelopmental outcome at 2 years of age in infants born with FGR with placental dysfunction, as compared with children with FGR with no signs of placental insufficiency (17) and markedly different placentas (increased number of trophoblast inclusions) in fetuses with increased risk for autism (18). Assessment of these changes using the omics approaches would allow for the description of placental molecular characteristics and possible identification of neonates at risk for neurodevelopmental disabilities (10).
Omics technologies applied to human placenta
Biochemistry studies have provided an immense collection of data related to the separate components of biological systems and their associated function (19). These include information related to genes, transcripts, proteins, and metabolites. The placenta is a transient organ that serves the needs of the growing fetus, but its functioning has effects on health, which extend far beyond its own life span (20). It has recently been postulated that understanding the biology of the human placenta requires a comprehensive and inclusive approach, which embraces all the biomedical disciplines and omics technologies and then integrates information obtained from all of them (10,21). Risk assessment and diagnostic tests that are based on mathematical algorithms that combine information from multiple variables into a single probability index are fundamental to the delivery of precision medicine. Platform technologies that deliver multivariate and multiplex data, such as omics, are pivotal in delivering such outcomes (21). The adoption of omics technologies to study the human placenta is relatively recent.
The genome represents the total complement of genes and genetic material within a biological system (21). Genomics applies DNA technology (recombination and sequencing) to identify genome structure and function (21). Recent data indicate that changes in placental gene expression are conveyed to the developing fetus to influence formation and function of neuronal circuits (6). In response to acute maternal food deprivation, Broad and Keverne demonstrated that a program of catabolic gene expression is initiated in the placenta, whereas the hypothalamus is highly spared (22). The authors state that the fetus controls its own destiny in times of acute starvation by short-term sacrifice of the placenta to preserve brain development (22). Human and animal studies have demonstrated timing-dependent effects of maternal stress on placental size, efficiency, and gene expression (7). Recent studies using transgenic mouse lines to selectively target stress-sensitive placental genes were able to recapitulate the effects of prenatal stress on hypothalamic programming and function, providing strong evidence for the critical role of placental function for brain development (23,24).
Epigenomics is the study of heritable but feasibly environmentally modifiable control of gene expression potential without DNA sequence changes (25). Changes that alter genome function include DNA methylation, histone methylation, acetylation and phosphorylation, and changes in small noncoding RNA expression (21). Placental methylation is quite distinct from somatic tissues; while globally decreased, methylation is higher at some regions (26). The placenta is also unique among normal tissues in the presence of “partially methylated domains,” a large sequence along the chromosomes that show distinctly lower methylation (27). Application of array- and sequencing-based technologies can identify differences between pathological and normal placentas, for example, early onset preeclampsia (PE) is associated with a unique methylation profile (27). More interestingly, the detection of more subtle changes may be associated with maternal exposures, such as maternal stress and diet (27).
Epigenomic remodeling is increasingly recognized as a molecular bridge linking placental adaptive responses to adversity with long-term outcomes (26). Due to its role in neuroendocrine regulation and development, the placenta has been described as a “third brain” that links the developing fetal brain and the mature maternal brain (28) and is, thus, a sensitive functional tissue to understand the prenatal environmental effects on neurodevelopment (29).