ArticleLiterature Review

Epigenetic mechanisms in the placenta related to infant neurodevelopment

Epigenomics

January 2018
10(7014)

DOI:10.2217/epi-2016-0171

Authors:

Carmen J Marsit

Emory University

As the 'third brain' the placenta links the developing fetal brain and the maternal brain enabling study of epigenetic process in placental genes that affect infant neurodevelopment. We described the characteristics and findings of the 17 studies on epigenetic processes in placental genes and human infant neurobehavior. Studies showed consistent findings in the same cohort of term healthy infants across epigenetic processes (DNA methylation, genome wide, gene and miRNA expression) genomic region (single and multiple genes, imprinted genes and miRNAs) using candidate gene and genome wide approaches and across biobehavioral systems (neurobehavior, cry acoustics and neuroendocrine). Despite limitations, studies support future work on molecular processes in placental genes related to neurodevelopmental trajectories including implications for intervention.

Post-translational histone modifications and their interaction with sex influence normal brain development and elaboration of neuropsychiatric disorders

Article

Oct 2018
BBA-MOL BASIS DIS

Sex differences in the risk for and expression of various brain disorders have been known for some time. Yet, the molecular underpinnings of these sex differences as well as how sex modifies normal brain development are still poorly understood. It has recently become known that epigenetic mechanisms play an essential role in establishing and maintaining sex differences in neurodevelopment and disease susceptibility. Epigenetic mechanisms such as post-translational modifications of histones (histone PTMs) integrate various hormonal and external environmental influences to affect genomic output, and this appears to occur in a sex-dependent manner. The present review aims to highlight current understanding of the role of histone PTMs in the sexual differentiation of the brain under normal conditions and how sex-specific modulation of histone PTMs may be involved in psychiatric conditions including autism spectrum disorder (ASD), schizophrenia, and major depressive disorder (MDD). The role of sex chromosome genes as sex-specific histone modifiers and their importance in sexually differentiating the brain will be discussed. Further, the contribution of sex-specific histone PTM marks in the placenta in programming the sexually dimorphic developmental course of the brain and susceptibility to diseases/disorders will be reviewed. Prenatal programming may have a long-lasting effect on the adult brain and behavior but due to the interaction of histone PTMs and its modifiers with fluctuating hormone levels and external influences over the lifespan, the process remains dynamic. Although a few studies indicate an association between sex and histone PTM-related mechanisms in ASD, schizophrenia, and MDD, more research is needed to fully appreciate the interactive effects of histone PTMs and sex in the development and manifestation of these disorders. Understanding the interactions between sex and histone PTMs will advance our understanding of psychiatric disorders and potentially guide development of future treatments tailored specifically to each sex.

Mental Health Epigenetics: A Primer With Implications for Counselors

Article

Full-text available

Mar 2021

Epigenetics is the study of modifications to gene expression without an alteration to the DNA sequence. Currently there is limited translation of epigenetics to the counseling profession. The purpose of this article is to inform counseling practitioners and counselor educators about the potential role epigenetics plays in mental health. Current mental health epigenetic research supports that adverse psychosocial experiences are associated with mental health disorders such as schizophrenia, anxiety, depression, and addiction. There are also positive epigenetic associations with counseling interventions, including cognitive behavioral therapy, mindfulness, diet, and exercise. These mental health epigenetic findings have implications for the counseling profession such as engaging in early life span health prevention and wellness, attending to micro and macro environmental influences during assessment and treatment, collaborating with other health professionals in epigenetic research, and incorporating epigenetic findings into counselor education curricula that meet the standards of the Council for Accreditation of Counseling and Related Educational Programs (CACREP).

Fetal cardiovascular magnetic resonance imaging

Article

Full-text available

Dec 2020
PEDIATR RADIOL

Fetal cardiovascular MRI is showing promise as a clinical diagnostic tool in the setting of congenital heart disease when the cardiac anatomy is unresolved by US or when complementary quantitative data on blood flow, oxygen saturation and hematocrit are required to aid in management. Compared with postnatal cardiovascular MRI, prenatal cardiovascular MRI still has some technical limitations. However, ongoing technical advances continue to improve the robustness and usability of fetal cardiovascular MRI. In this review, we provide an overview of the state of the art of fetal cardiovascular MRI and summarize the current focus of clinical application for this versatile technique.

A Behavioral Epigenetics Model to Predict Oral Feeding Skills in Preterm Infants

Article

Feb 2020
Adv Neonatal Care

Background: Preterm infants experience a multitude of prenatal and postnatal stressors, resulting in cumulative stress exposure, which may jeopardize the timely attainment of developmental milestones, such as achieving oral feeding. Up to 70% of preterm infants admitted to the neonatal intensive care unit experience challenges while initiating oral feeding. Oral feeding skills require intact neurobehavioral development. Evolving evidence demonstrates that cumulative stress exposure results in epigenetic modification of glucocorticoid-related genes. Epigenetics is a field of study that focuses on phenotypic changes that do not involve alterations in the DNA sequence. Epigenetic modification of glucocorticoid-related genes alters cortisol reactivity to environmental stimuli, which may influence neurobehavioral development, and is the essence of the evolving field of Preterm Behavioral Epigenetics. It is plausible that early-life cumulative stress exposure and the ensuing epigenetic modification of glucocorticoid-related genes impair neurobehavioral development required for achievement of oral feeding skills in preterm infants. Purpose: The purpose of this article is to build upon the evolving science of Preterm Behavioral Epigenetics and present a conceptual model that explicates how cumulative stress exposure affects neurobehavioral development and achievement of oral feeding skills through epigenetic modification of glucocorticoid-related genes. Methods/results: Using the Preterm Behavioral Epigenetics framework and supporting literature, we present a conceptual model in which early-life cumulative stress exposure, reflected by DNA methylation of glucocorticoid-related genes and altered cortisol reactivity, disrupts neurobehavioral development critical for achievement of oral feeding skills. Implications for practice and research: Future investigations guided by the proposed conceptual model will benefit preterm infant outcomes by introducing epigenetic-based approaches to assess and monitor preterm infant oral feeding skills. Furthermore, the proposed model can guide future investigations that develop and test epigenetic protective interventions to improve clinical outcomes, representing an innovation in neonatal care.

Independent and Combined Effects of Prenatal Alcohol Exposure and Prenatal Stress on Fetal HPA Axis Development

Article

Full-text available

Feb 2024
INT J MOL SCI

Prenatal alcohol exposure (PAE) and prenatal stress (PS) are highly prevalent conditions known to affect fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis. The objectives of this study were to assess the effect of light PAE, PS, and PAE-PS interaction on fetal HPA axis activity assessed via placental and umbilical cord blood biomarkers. Participants of the ENRICH-2 cohort were recruited during the second trimester and classified into the PAE and unexposed control groups. PS was assessed by the Perceived Stress Scale. Placental tissue was collected promptly after delivery; gene and protein analysis for 11β-HSD1, 11β-HSD2, and pCRH were conducted by qPCR and ELISA, respectively. Umbilical cord blood was analyzed for cortisone and cortisol. Pearson correlation and multivariable linear regression examined the association of PAE and PS with HPA axis biomarkers. Mean alcohol consumption in the PAE group was ~2 drinks/week. Higher PS was observed in the PAE group (p < 0.01). In multivariable modeling, PS was associated with pCRH gene expression (β = 0.006, p < 0.01), while PAE was associated with 11β-HSD2 protein expression (β = 0.56, p < 0.01). A significant alcohol-by-stress interaction was observed with respect to 11β-HSD2 protein expression (p < 0.01). Results indicate that PAE and PS may independently and in combination affect fetal programming of the HPA axis.

Placental inflammatory cytokines mRNA expression and preschool children’s cognitive performance: a birth cohort study in China

Article

Full-text available

Nov 2023
BMC MED

Background The immunologic milieu at the maternal–fetal interface has profound effects on propelling the development of the fetal brain. However, accessible epidemiological studies concerning the association between placental inflammatory cytokines and the intellectual development of offspring in humans are limited. Therefore, we explored the possible link between mRNA expression of inflammatory cytokines in placenta and preschoolers’ cognitive performance. Methods Study subjects were obtained from the Ma’anshan birth cohort (MABC). Placental samples were collected after delivery, and real-time quantitative polymerase chain reaction (RT-qPCR) was utilized to measure the mRNA expression levels of IL-8, IL-1β, IL-6, TNF-α, CRP, IFN-γ, IL-10, and IL-4. Children’s intellectual development was assessed at preschool age by using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV). Multiple linear regression and restricted cubic spline models were used for statistical analysis. Results A total of 1665 pairs of mother and child were included in the analysis. After adjusting for confounders and after correction for multiple comparisons, we observed that mRNA expression of IL-8 (β = − 0.53; 95% CI, − 0.92 to − 0.15), IL-6 (β = − 0.58; 95% CI, − 0.97 to − 0.19), TNF-α (β = − 0.37; 95% CI, − 0.71 to − 0.02), and IFN-γ (β = − 0.31; 95% CI, − 0.61 to − 0.03) in the placenta was negatively associated with preschoolers’ full scale intelligence quotient (FSIQ). Both higher IL-8 and IL-6 were associated with lower children’s low fluid reasoning index (FRI), and higher IFN-γ was associated with lower children’s working memory index (WMI). After further adjusting for confounders and children’s age at cognitive testing, the integrated index of six pro-inflammatory cytokines (index 2) was found to be significantly and negatively correlated with both the FSIQ and each sub-dimension (verbal comprehension index (VCI), visual spatial index (VSI), FRI, WMI, processing speed index (PSI)). Sex-stratified analyses showed that the association of IL-8, IFN-γ, and index 2 with children’s cognitive development was mainly concentrated in boys. Conclusions Evidence of an association between low cognitive performance and high expression of placental inflammatory cytokines (IL-8, IL-6, TNF-α, and IFN-γ) was found, highlighting the potential importance of intrauterine placental immune status in dissecting offspring cognitive development.

High-Dimensional Mediation Analysis: A New Method Applied to Maternal Smoking, Placental DNA Methylation, and Birth Outcomes

Article

Full-text available

Apr 2023
ENVIRON HEALTH PERSP

Background: High-dimensional mediation analysis is an extension of unidimensional mediation analysis that includes multiple mediators, and increasingly it is being used to evaluate the indirect omics-layer effects of environmental exposures on health outcomes. Analyses involving high-dimensional mediators raise several statistical issues. Although many methods have recently been developed, no consensus has been reached about the optimal combination of approaches to high-dimensional mediation analyses. Objectives: We developed and validated a method for high-dimensional mediation analysis (HDMAX2) and applied it to evaluate the causal role of placental DNA methylation in the pathway between exposure to maternal smoking (MS) during pregnancy and gestational age (GA) and birth weight of the baby at birth. Methods: HDMAX2 combines latent factor regression models for epigenome-wide association studies with max2 tests for mediation and considers CpGs and aggregated mediator regions (AMRs). HDMAX2 was carefully evaluated using simulated data and compared to state-of-the-art multidimensional epigenetic mediation methods. Then, HDMAX2 was applied to data from 470 women of the Etude des Déterminants pré et postnatals du développement de la santé de l'Enfant (EDEN) cohort. Results: HDMAX2 demonstrated increased power in comparison with state-of-the-art multidimensional mediation methods and identified several AMRs not identified in previous mediation analyses of exposure to MS on birth weight and GA. The results provided evidence for a polygenic architecture of the mediation pathway with a posterior estimate of the overall indirect effect of CpGs and AMRs equal to 44.5g lower birth weight representing 32.1% of the total effect [standard deviation (SD)=60.7g]. HDMAX2 also identified AMRs having simultaneous effects both on GA and on birth weight. Among the top hits of both GA and birth weight analyses, regions located in COASY, BLCAP, and ESRP2 also mediated the relationship between GA and birth weight, suggesting reverse causality in the relationship between GA and the methylome. Discussion: HDMAX2 outperformed existing approaches and revealed an unsuspected complexity of the potential causal relationships between exposure to MS and birth weight at the epigenome-wide level. HDMAX2 is applicable to a wide range of tissues and omic layers. https://doi.org/10.1289/EHP11559.

Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders

Preprint

Full-text available

Mar 2023

Increasing evidence supports the role of placenta in neurodevelopment and potentially, in the later onset of neuropsychiatric disorders. Recently, methylation quantitative trait loci (mQTL) and interaction QTL (iQTL) maps have proven useful to understand SNP-genome wide association study (GWAS) relationships, otherwise missed by conventional expression QTLs. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation (DNAm). We constructed the first public placental cis-mQTL database including nearly eight million mQTLs calculated in 368 fetal placenta DNA samples from the INMA project, ran cell type-and gestational age-imQTL models and combined those data with the summary statistics of the largest GWAS on 10 neuropsychiatric disorders using Summary-based Mendelian Randomization (SMR) and colocalization. Finally, we evaluated the influence of the DNAm sites identified on placental gene expression in the RICHS cohort. We found that placental cis-mQTLs are highly enriched in placenta-specific active chromatin regions, and useful to map the etiology of neuropsychiatric disorders at prenatal stages. Specifically, part of the genetic burden for schizophrenia, bipolar disorder and major depressive disorder confers risk through placental DNAm. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, regional pleiotropic methylation signals associated to the same disorder, and cell type-imQTLs, additionally associated to the expression levels of relevant immune genes in placenta. In conclusion, the genetic risk of several neuropsychiatric disorders could operate, at least in part, through DNAm and associated gene expression in placenta.

Epigenetic histone acetylation modulating prenatal Poly I:C induced neuroinflammation in the prefrontal cortex of rats: a study in a maternal immune activation model

Article

Full-text available

Nov 2022

Introduction: Neuroinflammation in the central nervous system, particularly the prefrontal cortex (PFC), plays a role in the pathogenesis of schizophrenia, which has been found to be associated with maternal immune activation (MIA). Recent evidence suggests that epigenetic regulation involves in the MIA-induced neurodevelopmental disturbance. However, it is not well-understood how epigenetic modulation is involved in the neuroinflammation and pathogenesis of schizophrenia. Methods: This study explored the modulation of histone acetylation in both neuroinflammation and neurotransmission using an MIA rat model induced by prenatal polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure, specifically examining those genes that were previously observed to be impacted by the exposure, including a subunit of nuclear factor kappa-B ( Rela ), Nod-Like-Receptor family Pyrin domain containing 3 ( Nlrp3 ), NMDA receptor subunit 2A ( Grin2a ), 5-HT2A ( Htr2a ), and GABAA subunit β3 ( Gabrb3 ). Results: Our results revealed global changes of histone acetylation on H3 (H3ace) and H4 (H4ace) in the PFC of offspring rats with prenatal Poly I:C exposure. In addition, it revealed enhancement of both H3ace and H4ace binding on the promoter region of Rela , as well as positive correlations between Rela and genes encoding histone acetyltransferases (HATs) including CREB-binding protein (CBP) and E1A-associated protein p300 (EP300). Although there was no change in H3ace or H4ace enrichment on the promoter region of Nlrp3 , a significant enhancement of histone deacetylase 6 (HDAC6) binding on the promoter region of Nlrp3 and a positive correlation between Nlrp3 and Hdac6 were also observed. However, prenatal Poly I:C treatment did not lead to any specific changes of H3ace and H4ace on the promoter region of the target genes encoding neurotransmitter receptors in this study. Discussion: These findings demonstrated that epigenetic modulation contributes to NF-κB/NLRP3 mediated neuroinflammation induced by prenatal Poly I:C exposure via enhancement of histone acetylation of H3ace and H4ace on Rela and HDAC6-mediated NLRP3 transcriptional activation. This may further lead to deficits in neurotransmissions and schizophrenia-like behaviors observed in offspring.

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

Article

Full-text available

Oct 2022

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.

Associations of Mitochondrial Function, Stress, and Neurodevelopmental Outcomes in Early Life: A Systematic Review

Article

Aug 2022

Early life stress is commonly experienced by infants, especially preterm infants that may impact their neurodevelopmental outcomes in their early and later life. Mitochondrial function/dysfunction may play an important role underlying the linkage of prenatal and postnatal stress and neurodevelopmental outcomes in infants. This review aims to provide insights on the relationship between early life stress and neurodevelopment, and the mechanisms of mitochondrial function/dysfunction that contribute to the neuropathology of stress. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement was used to develop this systematic review. PubMed, Scopus, PsycINFO, and Biosis databases were searched for primary research articles published between 2010-2021 that examined the relationships among mitochondrial function/dysfunction, infant stress, and neurodevelopment. Thirty studies were identified. There is evidence to support that mitochondrial function/dysfunction mediates the relationship between prenatal and postnatal stress and neurodevelopmental outcomes in infants. Maternal transgenerational transmission of mitochondrial bioenergetic patterns influenced prenatal stress induced neurodevelopmental outcomes and behavioral changes in infants. Multiple functionally relevant mitochondrial proteins, genes and polymorphisms were associated with stress exposure. This is the first review of the role that mitochondrial function/dysfunction plays in the association between stress and neurodevelopmental outcomes in full-term and preterm infants. Although multiple limitations were found based on the lack of data on the influence of biological sex, and due to invasive sampling, and lack of longitudinal data, many genes and proteins associated with mitochondrial function/dysfunction were found to influence neurodevelopmental outcomes in the early life of infants.

Sex differences in human perinatal development and autism

Thesis

Nov 2021

Alex Tsompanidis

Autism is a neurodevelopmental condition that is more frequently diagnosed in males than females. To explain this, in 2014, the prenatal sex steroid theory was proposed. This extended the fetal testosterone theory, published in 2004. The prenatal sex steroid theory proposes that exposure to higher levels of prenatal sex steroids (e.g., prenatal androgens and estrogens) that are on average higher in male fetuses are associated with higher likelihood for autism and elevated autistic traits. This background literature is reported in Chapter 1. In this thesis, eight novel studies are reported that test and extend the prenatal sex steroid theory by investigating perinatal factors related to sex differences in physiology. Study 1 (described in Chapter 2) reports a case-control analysis of steroid levels in the amniotic fluid of males who were later diagnosed as autistic, linked with the Danish Biobank (n = 98 cases, n = 177 controls). This included univariate analyses of both prenatal androgens and estrogens, as well as the aromatisation ratio. All estrogens, but not testosterone, on average were elevated in autistic males. Study 2 (described in Chapter 3) reports a prospective cohort study (the Cambridge Ultrasound and Pregnancy [CUSP] study) of pregnant women and their infants in Cambridge (n=219), who were assessed for their autistic traits during pregnancy and late infancy. Steroid hormone levels were assessed in maternal serum. Estradiol levels correlated with both maternal autistic traits and the male infants’ autistic traits, but there was no correlation with female infants’ autistic traits. Study 3 (described in Chapter 4) reports a large prospective cohort study in Rotterdam (Generation-R) that studied the levels of placental function markers in maternal serum (n=3469), their sex differences in the general population, their association with both autistic traits in childhood (assessed using the Social Responsiveness Scale - SRS), and with likelihood for autism in males. Male-like patterns in placental angiogenic markers, high placental growth factor (PlGF) and low soluble fms-like tyrosine kinase-1 (sFlt-1) levels, respectively correlated with higher autistic traits in females and an autism diagnosis in males. Chapter 5 describes Studies 4, 5, and 6, all based on a longitudinal cohort, the Cambridge Human Infant Longitudinal Development [CHILD] Study. This included prenatal (n=41) and postnatal (n=27) brain MRI imaging and salivary testosterone measurements during mini-puberty. Study 4 found that both male and female infants experienced transient increases in testosterone postnatally (2 to 6 months), but this did not correlate to their autistic traits at 18 months. Study 5 focused on total brain volume and surface area in infancy, as well as rate of brain growth perinatally, all of which correlated negatively with the infant’s autistic traits. Study 6 found that this was driven by low volume in regions that show sex differences and are involved in face recognition. Chapter 6 describes two genetic studies, which found that autism-related genetic variance (rare and common variance respectively) overlaps with X-linked genes that show sex differences in the placenta (Study 7) and correlates with the genetics for early age of menarche (Study 8). Chapter 7 brings all of the findings from Studies 1 to 8 together to draw conclusions and consider limitations and future directions. Based on these analyses, I then propose a new theory on the role of the placenta in mediating sex differences in human perinatal development and autism.

Fetal neurosonography and infant neurobehavior in assisted reproductive technologies following fresh and frozen embryo transfer

Article

Apr 2022

Objective: To explore and compare fetal cortical brain development and infant neurobehaviour in spontaneously conceived (SC) and assisted reproductive technologies (ART) offspring. Methods: A prospective cohort study of 210 singleton pregnancies including 70 SC pregnancies, 70 conceived by in vitro fertilization (IVF) following frozen embryo transfer (ET), and 70 IVF after fresh ET. Fetal neurosonography was performed at 32±2 weeks to assess cortical development. Sulci depths were measured off-line and normalized by biparietal diameter. Additionally, Ages & Stages Questionnaires (ASQ) were obtained postnatally, at 12±1 months of corrected age. Comparisons were adjusted by maternal age, ethnicity, nulliparity, fetal sex, weight centile and gestational age at scan for neurosonography, and by maternal age, ethnicity, nulliparity, educational level, employment status, new-born's gestational age at birth, breastfeeding, infant's sex and age at the ASQ evaluation. Results: In comparison to the SC, the fetuses conceived by ART showed statistically significant differences in cortical development, with reduced parieto-occipital (fresh ET mean[SD] 12.5mm[2.5] vs. frozen ET 13.4[2.6] vs. SC 13.4[2.6], p<0.001), cingulate (fresh ET 5.8[1.8] vs. frozen ET 6.0[2.1] vs. SC 6.4[1.9], p<0.001), and calcarine (fresh ET 13.3[3.9] vs. frozen ET 14.1[2.8] vs. SC 16.1[2.7], p=<0.001) sulci depth, together with lower Sylvian fissure grading score. Changes in cortical development were more pronounced in the fresh ET group as compared to the frozen ET. Additionally, ART infants showed lower ASQ scores, especially in the fresh ET group (global ASQ z-scores: fresh ET mean[SD] -0.3[0.4] vs. frozen ET -0.2[0.4] vs. SC 0[0.4], p<0.001). Conclusions: Fetuses conceived by ART show a distinctive pattern of cortical development and suboptimal infant neurodevelopment, with more pronounced changes in fresh ET. These findings support the existence of in utero brain reorganization associated to ART and warrant follow-up studies to assess their long-term persistence. This article is protected by copyright. All rights reserved.

HDMAX2: A framework for High Dimensional Mediation Analysis with application to maternal smoking, placental DNA methylation and birth outcomes

Preprint

Full-text available

Mar 2022

Background High-dimensional mediation analysis is an extension of unidimensional mediation analysis that includes multiple mediators, and is increasingly used to evaluate the indirect omics-layer effects of environmental exposures on health outcomes. Analyses involving high-dimensional mediators raise several statistical issues. While many methods have recently been developed, no consensus has been reached about the optimal combination of approaches to high-dimensional mediation analyses. Objectives We developed and validated a method for high-dimensional mediation analysis (HDMAX2) and applied it to evaluate the causal role of placental DNA methylation in the pathway between exposure to maternal smoking (MS) during pregnancy and gestational age (GA) and weight (BW) of the baby at birth. Methods HDMAX2 combines latent factor regression models for epigenome-wide association studies with max-squared tests for mediation, and considers CpGs and aggregated mediator regions (AMR). HDMAX2 was carefully evaluated on simulated data, and compared to state-of-the-art multi-dimensional epigenetic mediation methods. Then HDMAX2 was applied on data from 470 women of the EDEN cohort. Results HDMAX2 demonstrated increased power compared to state-of-the-art multi-dimensional mediation methods, and identified several AMRs not identified in previous mediation analyses of exposure to MS on BW and GA. The results provided evidence for a polygenic architecture of the mediation pathway with an overall indirect effect of CpGs and AMRs of 44.5 g lower BW (32.1% of the total effect). HDMAX2 also identified AMRs having simultaneous effects both on GA and on BW. Among the top hits of both GA and BW analyses, regions located in COASY, BLCAP and ESRP2 also mediated the relationship between GA on BW, suggesting a reverse causality in the relationship between GA and the methylome. Discussion HDMAX2 outperformed existing approaches and revealed an unsuspected complexity of the causal relationships between exposure to MS and BW at the epigenome-wide level. HDMAX2 is applicable to a wide range of tissues and omic layers.

Downregulation of Transcriptional Activity, Increased Inflammation, and Damage in the Placenta Following in utero Zika Virus Infection Is Associated With Adverse Pregnancy Outcomes

Article

Full-text available

Feb 2022

Zika virus (ZIKV) infection during pregnancy causes serious adverse outcomes to the developing fetus, including fetal loss and birth defects known as congenital Zika syndrome (CZS). The mechanism by which ZIKV infection causes these adverse outcomes, and specifically the interplay between the maternal immune response and ZIKV replication has yet to be fully elucidated. Using an immunocompetent mouse model of transplacental ZIKV transmission and adverse pregnancy outcomes, we have previously shown that Asian lineage ZIKV disrupts placental morphology and induces elevated secretion of IL-1β. In the current manuscript, we characterized placental damage and inflammation during in utero African lineage ZIKV infection. Within 48 h after ZIKV infection at embryonic day 10, viral RNA was detected in placentas and fetuses from ZIKA infected dams, which corresponded with placental damage and reduced fetal viability as compared with mock infected dams. Dams infected with ZIKV had reduced proportions of trophoblasts and endothelial cells and disrupted placental morphology compared to mock infected dams. While placental IL-1β was increased in the placenta, but not the spleen, within 3 h post infection, this was not caused by activation of the NLRP3 inflammasome. Using bulk mRNAseq from placentas of ZIKV and mock infected dams, ZIKV infection caused profound downregulation of the transcriptional activity of genes that may underly tissue morphology, neurological development, metabolism, cell signaling and inflammation, illustrating that in utero ZIKV infections causes disruption of pathways associated with CZS in our model.

Reliability of a novel approach for reference-based cell type estimation in human placental DNA methylation studies

Article

Full-text available

Feb 2022
CELL MOL LIFE SCI

The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta, however, an assessment of the performance of these estimation methods is still lacking. Here, we examine the performance of a newly available reference-based cell type estimation approach and compare it to an often-used reference-free cell type estimation approach, namely RefFreeEWAS, in placental genome-wide DNAm samples taken at birth and from chorionic villus biopsies early in pregnancy using three independent studies comprising over 1000 samples. We found both reference-free and reference-based estimated cell type proportions to have predictive value for DNAm, however, reference-based cell type estimation outperformed reference-free estimation for the majority of data sets. Reference-based cell type estimations mirror previous histological knowledge on changes in cell type proportions through gestation. Further, CpGs whose variation in DNAm was largely explained by reference-based estimated cell type proportions were in the proximity of genes that are highly tissue-specific for placenta. This was not the case for reference-free estimated cell type proportions. We provide a list of these CpGs as a resource to help researchers to interpret results of existing studies and improve future DNAm studies of human placenta.

Prenatal Lead and Depression Exposures Jointly Influence Birth Outcomes and NR3C1 DNA Methylation

Article

Full-text available

Nov 2021
Int J Environ Res Publ Health

Many gestational exposures influence birth outcomes, yet the joint contribution of toxicant and psychosocial factors is understudied. Moreover, associated gestational epigenetic mechanisms are unknown. Lead (Pb) and depression independently influence birth outcomes and offspring NR3C1 (glucocorticoid receptor) DNA methylation. We hypothesized that gestational Pb and depression would jointly influence birth outcomes and NR3C1 methylation. Pregnancy exposure information, DNA methylation, and birth outcome data were collected prospectively from n = 272 mother–infant pairs. Factor analysis was used to reduce the dimensionality of NR3C1. Multivariable linear regressions tested for interaction effects between gestational Pb and depression exposures with birth outcomes and NR3C1. Interaction effects indicated that higher levels of Pb and depression jointly contributed to earlier gestations, smaller infant size at birth, and asymmetric fetal growth. Pb and depression were also jointly associated with the two primary factor scores explaining the most variability in NR3C1 methylation; NR3C1 scores were associated with some infant outcomes, including gestational age and asymmetric fetal growth. Pb and depression can cumulatively influence birth outcomes and epigenetic mechanisms, which may lay the foundation for later health risk. As toxicants and social adversities commonly co-occur, research should consider the life course consequences of these interconnected exposures.

Potential roles of imprinted genes in the teratogenic effects of alcohol on the placenta, somatic growth, and the developing brain

Article

Nov 2021
EXP NEUROL

Despite several decades of research and prevention efforts, fetal alcohol spectrum disorders (FASD) remain the most common preventable cause of neurodevelopmental disabilities worldwide. Animal and human studies have implicated fetal alcohol-induced alterations in epigenetic programming as a chief mechanism in FASD. Several studies have demonstrated fetal alcohol-related alterations in methylation and expression of imprinted genes in placental, brain, and embryonic tissue. Imprinted genes are epigenetically regulated in a parent-of-origin-specific manner, in which only the maternal or paternal allele is expressed, and the other allele is silenced. The chief functions of imprinted genes are in placental development, somatic growth, and neurobehavior—three domains characteristically affected in FASD. In this review, we summarize the growing body of literature characterizing these changes and discuss potential mechanistic roles for alterations in imprinted gene methylation and/or expression in the teratogenic effects of prenatal alcohol exposure. Future research is needed to examine potential physiologic mechanisms by which alterations in imprinted genes disrupt development in FASD, which may, in turn, elucidate novel targets for intervention. Furthermore, mechanistic alterations in imprinted gene expression and/or methylation in FASD may inform screening assays that identify individuals with FASD neurobehavioral deficits who may benefit from early interventions.

Impact of Depression and Stress on Placental DNA Methylation in Ethnically Diverse Pregnant Women

Article

Sep 2021

Aim: To investigate the association between placental genome-wide methylation at birth and antenatal depression and stress during pregnancy. Methods: We examined the association between placental genome-wide DNA methylation (n = 301) and maternal depression and stress assessed at six gestation periods during pregnancy. Correlation between DNA methylation at the significantly associated CpGs and expression of nearby genes in the placenta was tested. Results: Depression and stress were associated with methylation of 16 CpGs and two CpGs, respectively, at a 5% false discovery rate. Methylation levels at two of the CpGs associated with depression were significantly associated with expression of ADAM23 and CTDP1, genes implicated in neurodevelopment and neuropsychiatric diseases. Conclusion: Placental epigenetic changes linked to antenatal depression suggest potential fetal brain programming. Clinical trial registration number: NCT00912132 (ClinicalTrials.gov)

Reference-Based Versus Reference-Free Cell Type Estimation In DNA Methylation Studies Using Human Placental Tissue

Preprint

Full-text available

Aug 2021

The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta, however, an assessment of the performance of these estimation methods is still lacking. Here, we compare the predictive performance of reference-based versus reference-free estimated proportions of cell types from genome-wide DNAm in placental samples taken at birth and from chorion villus biopsies early in pregnancy using three independent studies comprising over 1,000 samples. We found both reference-free and reference-based estimated cell type proportions to have predictive value for DNAm, however, reference-based cell type estimation outperformed reference-free estimation for the majority of data sets. Reference-based cell type estimations mirror previous histological knowledge on changes in cell type proportions through gestation. Further, CpGs whose variation in DNAm was largely explained by reference-based estimated cell type proportions were in the proximity of genes that are highly tissue-specific for placenta. This was not the case for reference-free estimated cell type proportions. We provide a list of these CpGs as a resource to help researchers to interpret results of existing studies and improve future DNAm studies of human placenta.

P-766 Neurodevelopment in fetuses conceived by assisted reproductive technologies following fresh and frozen embryo transfer

Article

Aug 2021

Study question Do in vitro fertilization (IVF) offspring present different neurodevelopment assessed by fetal neurosonography and infant neurobehavioral tests as compared to those spontaneously conceived (SC)? Summary answer IVF offspring, especially those obtained after fresh embryo-transfer (ET), showed subtle structural differences in fetal neurosonography and poorer neurobehavioral scores at twelve months of age. What is known already The number of pregnancies following assisted reproductive technologies (ART) is currently increasing worldwide. Concerns about the neurodevelopment of subjects conceived by IVF have been rising and mostly studied in children and adolescents with inconsistent results. Many of the identified risk associations were only observed in subgroups or disappeared after adjustment for covariates, mainly multiple pregnancy and gestational age at birth. It is unknown whether fetal brain development and cortical folding differ prenatally in IVF fetuses as compared to SC. Study design, size, duration This is the first study examining fetal neurodevelopment by neurosonography in IVF fetuses. A prospective cohort study of 210 singleton pregnancies recruited from 2017 to 2020, including 70 SC gestations, 70 conceived by IVF following frozen ET (FET) and 70 IVF after fresh ET. Fetal neurosonography was performed in all pregnancies. Additionally, Ages & Stages Questionnaires (ASQ) were obtained at 12 months of corrected age. Participants/materials, setting, methods IVF pregnancies were recruited from a single Assisted Reproduction Center, ensuring homogeneity in IVF stimulation protocols, endometrial preparation, laboratory procedures and embryo culture conditions. SC pregnancies were randomly selected from low-risk fertile couples and paired to IVF by maternal age. Fetal neurosonography including transvaginal approach was performed at 32±2 weeks of gestation, measured off-line by a single investigator and normalized by biparietal or occipitofrontal diameter. ASQ were obtained postnatally, at 12 months of corrected age. Main results and the role of chance Study groups were similar and comparable regarding maternal age, body mass index, study level and employment rate together with exposure to smoke, alcohol, aspirin and corticoids during pregnancy, gestational age (32±2 weeks) and estimated fetal weight (1700±400g) at neurosonography. As compared to SC pregnancies, both IVF populations showed differences in cortical development with reduced parieto-occipital (fresh ET 12.5mm [SD 2.5] vs FET 13.4 [2.6] vs SC 13.4 [2.6]), cingulate (fresh ET 5.8 [IQR 4.2-7.4] vs FET 5.8 [4.1-7.5] vs SC 6.5 [4.8-7.8]) and calcarine (fresh ET 13.5 [IQR 10.1-16.1] vs FET 14.5 [12.1-15.8] vs SC 16.4 [14.3-17.9]) sulci depth together with lower Sylvian fissure grading. Cortical development changes were more pronounced in the fresh ET group as compared to FET. Corpus callosum length and insula depth were lower in FET and fresh ET groups, respectively. Neurosonographic changes remained statistically significant after adjustment by ethnicity, gender, gestational age and weight centile at scan. IVF infants showed worse ASQ scores, especially in fresh ET for communication, personal-social, fine-motor and problem-solving skills. Gross-motor scores were significantly lower in FET as compared to SC and fresh ET. Differences were statistically significant after adjustment by maternal ethnicity, study level, employment status, breastfeeding, gender and corrected age. Limitations, reasons for caution The reported neurodevelopmental differences are subtle, with most neurosonographic findings lying within normal ranges. Infertility factors contribution to the outcome cannot be unraveled from the ART procedure itself. The milder features found in FET individuals cannot condition the techniqués choice and must be considered together with their global perinatal results. Wider implications of the findings Neurosonography is an appropriate tool to identify subtle brain differences between fetuses exposed and not exposed to ART. Prenatal features were consistent with postnatal neurobehavioral findings. These results support the relevance of a neurodevelopmental follow-up in IVF patients. Further studies are warranted to assess the long-term performance in these subjects. Trial registration number not applicable

P–766 Neurodevelopment in fetuses conceived by assisted reproductive technologies following fresh and frozen embryo transfer

Article

Full-text available

Aug 2021

Study question Do in vitro fertilization (IVF) offspring present different neurodevelopment assessed by fetal neurosonography and infant neurobehavioral tests as compared to those spontaneously conceived (SC)? Summary answer IVF offspring, especially those obtained after fresh embryo-transfer (ET), showed subtle structural differences in fetal neurosonography and poorer neurobehavioral scores at twelve months of age. What is known already The number of pregnancies following assisted reproductive technologies (ART) is currently increasing worldwide. Concerns about the neurodevelopment of subjects conceived by IVF have been rising and mostly studied in children and adolescents with inconsistent results. Many of the identified risk associations were only observed in subgroups or disappeared after adjustment for covariates, mainly multiple pregnancy and gestational age at birth. It is unknown whether fetal brain development and cortical folding differ prenatally in IVF fetuses as compared to SC. Study design, size, duration This is the first study examining fetal neurodevelopment by neurosonography in IVF fetuses. A prospective cohort study of 210 singleton pregnancies recruited from 2017 to 2020, including 70 SC gestations, 70 conceived by IVF following frozen ET (FET) and 70 IVF after fresh ET. Fetal neurosonography was performed in all pregnancies. Additionally, Ages & Stages Questionnaires (ASQ) were obtained at 12 months of corrected age. Participants/materials, setting, methods IVF pregnancies were recruited from a single Assisted Reproduction Center, ensuring homogeneity in IVF stimulation protocols, endometrial preparation, laboratory procedures and embryo culture conditions. SC pregnancies were randomly selected from low-risk fertile couples and paired to IVF by maternal age. Fetal neurosonography including transvaginal approach was performed at 32±2 weeks of gestation, measured off-line by a single investigator and normalized by biparietal or occipitofrontal diameter. ASQ were obtained postnatally, at 12 months of corrected age. Main results and the role of chance Study groups were similar and comparable regarding maternal age, body mass index, study level and employment rate together with exposure to smoke, alcohol, aspirin and corticoids during pregnancy, gestational age (32±2 weeks) and estimated fetal weight (1700±400g) at neurosonography. As compared to SC pregnancies, both IVF populations showed differences in cortical development with reduced parieto-occipital (fresh ET 12.5mm [SD 2.5] vs FET 13.4 [2.6] vs SC 13.4 [2.6]), cingulate (fresh ET 5.8 [IQR 4.2–7.4] vs FET 5.8 [4.1–7.5] vs SC 6.5 [4.8–7.8]) and calcarine (fresh ET 13.5 [IQR 10.1–16.1] vs FET 14.5 [12.1–15.8] vs SC 16.4 [14.3–17.9]) sulci depth together with lower Sylvian fissure grading. Cortical development changes were more pronounced in the fresh ET group as compared to FET. Corpus callosum length and insula depth were lower in FET and fresh ET groups, respectively. Neurosonographic changes remained statistically significant after adjustment by ethnicity, gender, gestational age and weight centile at scan. IVF infants showed worse ASQ scores, especially in fresh ET for communication, personal-social, fine-motor and problem-solving skills. Gross-motor scores were significantly lower in FET as compared to SC and fresh ET. Differences were statistically significant after adjustment by maternal ethnicity, study level, employment status, breastfeeding, gender and corrected age. Limitations, reasons for caution The reported neurodevelopmental differences are subtle, with most neurosonographic findings lying within normal ranges. Infertility factors contribution to the outcome cannot be unraveled from the ART procedure itself. The milder features found in FET individuals cannot condition the techniqués choice and must be considered together with their global perinatal results. Wider implications of the findings: Neurosonography is an appropriate tool to identify subtle brain differences between fetuses exposed and not exposed to ART. Prenatal features were consistent with postnatal neurobehavioral findings. These results support the relevance of a neurodevelopmental follow-up in IVF patients. Further studies are warranted to assess the long-term performance in these subjects. Trial registration number Not applicable

“The First Thousand Days” Define a Fetal/Neonatal Neurology Program

Article

Full-text available

Aug 2021

Mark S Scher

Gene–environment interactions begin at conception to influence maternal/placental/fetal triads, neonates, and children with short- and long-term effects on brain development. Life-long developmental neuroplasticity more likely results during critical/sensitive periods of brain maturation over these first 1,000 days. A fetal/neonatal program (FNNP) applying this perspective better identifies trimester-specific mechanisms affecting the maternal/placental/fetal (MPF) triad, expressed as brain malformations and destructive lesions. Maladaptive MPF triad interactions impair progenitor neuronal/glial populations within transient embryonic/fetal brain structures by processes such as maternal immune activation. Destructive fetal brain lesions later in pregnancy result from ischemic placental syndromes associated with the great obstetrical syndromes. Trimester-specific MPF triad diseases may negatively impact labor and delivery outcomes. Neonatal neurocritical care addresses the symptomatic minority who express the great neonatal neurological syndromes: encephalopathy, seizures, stroke, and encephalopathy of prematurity. The asymptomatic majority present with neurologic disorders before 2 years of age without prior detection. The developmental principle of ontogenetic adaptation helps guide the diagnostic process during the first 1,000 days to identify more phenotypes using systems-biology analyses. This strategy will foster innovative interdisciplinary diagnostic/therapeutic pathways, educational curricula, and research agenda among multiple FNNP. Effective early-life diagnostic/therapeutic programs will help reduce neurologic disease burden across the lifespan and successive generations.

Future Horizons for Neurodevelopmental Disorders: Placental Mechanisms

Article

Full-text available

Apr 2021

Placental origins of neonatal diseases: toward a precision medicine approach

Article

Full-text available

Dec 2020

The placenta is the single most reliable source for precise information on intrauterine environment, as well as maternal and fetal health. It mediates the physiology of two distinct yet highly interconnected individuals. The pathology that develops in the placenta, and the adaptations the placenta undergoes to mitigate this pathology, may influence the later life health of the mother and baby. Pathological placental examination provides a unique opportunity to explore and understand the intrauterine environment, as well as providing a record of events that may be associated with adverse pregnancy outcomes. A number of placental lesions have been described in association with various neonatal morbidities. The purpose of this review is to summarize the evidence for the association of placental pathologic lesions with neurodevelopmental outcomes infants with specific neonatal morbidities, including (1) neonatal encephalopathy, (2) bronchopulmonary dysplasia, (3) congenital heart diseases, and (4) autism spectrum disorders. For each of these disease processes, we will also propose specific research priorities in future studies. We conclude with a hospital-specific protocol for triaging which placentas should receive histological evaluation as a fundamental first step for the field of neuroplacentology to guide precision-based therapeutic approaches in the affected newborns. The purpose of this review is to summarize the evidence for placental origins of neonatal diseases. We propose specific research priorities in the field of neuroplacentology in future studies. We also present a targeted hospital-based approach for triaging which placentas should receive histological evaluation.

Effects of Vitrification on the Imprinted Gene Snrpn in Neonatal Placental Tissue

Article

Full-text available

Sep 2020

Jason Zhu

Objective: To investigate the effects of vitrification on the expression of the imprinted gene Snrpn in neonatal placental tissue.Methods: Neonatal placental tissue was collected from women with natural pregnancy (control group) and from women in assisted reproductive technology (ART) pregnancy group, following fresh and vitrified embryo transfer (fresh group and vitrified group, respectively). Snrpn mRNA expression and SNRPN protein levels in placental tissue from these three groups were assessed by real-time reverse transcription polymerase chain reaction and Western blot, respectively. DNA methylation in the Snrpn promoter region was analyzed by bisulfite-pyrosequencing.Results: The expression of Snrpn mRNA and SNRPN protein was found to be higher in placental tissue from the fresh and vitrified ART groups, compared to the control group. There was no significant difference in SNRPN gene or protein expression between the fresh and vitrified groups. DNA methylation at the Snrpn promoter region was not significantly different between these three groups.Conclusions: Human ART may alter the transcriptional expression and protein levels of the imprinted gene Snrpn. However, compared to other ART methods, vitrification may not aggravate or reduce this effect. Moreover, the altered expression of Snrpn is likely not directly related to DNA methylation of the Snrpn promoter region. Keywords: Assisted Reproductive Technology, Polymerase Chain Reaction, Snrpn Vitrification, Western Blot

Effects of Vitrification on the Imprinted Gene Snrpn in Neonatal Placental Tissue

Article

Full-text available

Jan 2020

Placenta and perinatal brain injury: the gateway to individualized therapeutics and precision neonatal medicine

Article

Feb 2020

Wu and colleagues analyzed the placental pathology from a subset of the neonates in the NEATO trial who had reports available and correlated the placental pathology findings with outcomes. This study highlights the importance of placental pathology, and its potential to bring precision medicine to critically-ill neonates. Placental pathology will likely aid stratification of neonates for clinical trials and accelerate progress for neurorepair.

Epigenome-Wide DNA Methylation in Placentas from Preterm Infants: Association with Maternal Socioeconomic Status

Article

Full-text available

May 2019

This study evaluated the hypothesis that prenatal maternal socioeconomic status (SES) adversity is associated with DNA methylation in the placenta. SES adversity was defined by the presence of, as well as a summative count of, the these factors: less than college education, single marital status, food and nutritional service assistance, and public health insurance. Epigenome-wide DNA methylation was assessed using the Illumina EPIC array in 426 placentas from a sample of infants born < 28 weeks of gestation from the Extremely Low Gestational Age Newborn cohort. Associations between SES adversity and DNA methylation were assessed with robust linear regressions adjusted for covariates and controlled the false discovery rate at < 10%. We also examined whether such associations were sex-specific. Indicators of SES adversity were associated with differential methylation at 33 CpG sites. Of the 33 identified CpG sites, 19 (57.6%) displayed increased methylation, and 14 (42.4%) displayed decreased methylation in association with at least one of the socioeconomic adversity factors. Sex differences were observed in DNA methylation associated with summative SES score; in which placentas derived from female pregnancies showed more robust differential CpG methylation than placentas from male pregnancies. Maternal SES adversity was associated with differential methylation of genes with key role in gene transcription and placental function, potentially altering immunity and stress response. Further investigation is needed to evaluate the role of epigenetic differences in mediating the association between maternal socioeconomic status during pregnancy and later life health outcomes in children.

Microorganisms in the Placenta: Links to Early-Life Inflammation and Neurodevelopment in Children

Article

May 2019

Prenatal exposure to various stressors can influence both early and later life childhood health. Microbial infection of the intrauterine environment, specifically within the placenta, has been associated with deleterious birth outcomes, such as preterm birth, as well as adverse neurological outcomes later in life. The relationships among microorganisms in the placenta, placental function, and fetal development are not well understood. Microorganisms have been associated with perinatal inflammatory responses that have the potential for disrupting fetal brain development. Microbial presence has also been associated with epigenetic modifications in the placenta, as well other tissues. Here we review research detailing the presence of microorganisms in the placenta and associations among such microorganisms, placental DNA methylation, perinatal inflammation, and neurodevelopmental outcomes.

Epigenome-wide Analysis Identifies Genes and Pathways Linked to Neurobehavioral Variation in Preterm Infants

Article

Full-text available

Apr 2019

Neonatal molecular biomarkers of neurobehavioral responses (measures of brain-behavior relationships), when combined with neurobehavioral performance measures, could lead to better predictions of long-term developmental outcomes. To this end, we examined whether variability in buccal cell DNA methylation (DNAm) associated with neurobehavioral profiles in a cohort of infants born less than 30 weeks postmenstrual age (PMA) and participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study (N = 536). We tested whether epigenetic age, age acceleration, or DNAm levels at individual loci differed between infants based on their NICU Network Neurobehavioral Scale (NNNS) profile classifications. We adjusted for recruitment site, infant sex, PMA, and tissue heterogeneity. Infants with an optimally well-regulated NNNS profile had older epigenetic age compared to other NOVI infants (β1 = 0.201, p-value = 0.026), but no significant difference in age acceleration. In contrast, infants with an atypical NNNS profile had differential methylation at 29 CpG sites (FDR < 10%). Some of the genes annotated to these CpGs included PLA2G4E, TRIM9, GRIK3, and MACROD2, which have previously been associated with neurological structure and function, or with neurobehavioral disorders. These findings contribute to the existing evidence that neonatal epigenetic variations may be informative for infant neurobehavior.

Examining the relationship between perinatal depression and neurodevelopment in infants and children through structural and functional neuroimaging research

Article

Full-text available

Jan 2019

Depression is the most common perinatal psychiatric disorder, but little is known about how it may impact offspring neurodevelopment, as well as the mechanisms by which it may confer transgenerational psychiatric risk. This review presents imaging studies conducted to evaluate the relationship between perinatal depression (PND) and infant and child neurodevelopment. Altered structural and functional connectivity is implicated in children exposed to PND and anxiety. Overall, there are changes in connectivity between amygdala and the prefrontal cortex. Studies suggest decreased hippocampal growth in the first 6 months after birth, decreased cortical thickness in children, and increased amygdala volumes, that are more pronounced in female offspring. Future research is needed to understand the impact of PND on development so that early interventions which promote mother–infant bonding and cognitive development may improve developmental outcomes in children exposed to PND, reducing later risk of psychopathology.

Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation

Article

Oct 2018

Purpose of Review Epigenetic processes represent important mechanisms underlying developmental plasticity in response to environmental exposures. The current review discusses three classes of environmentally induced epigenetic changes reflecting two aspects of that plasticity, toxicity effects as well as adaptation in the process of development. Recent Findings Due to innate resilience, epigenetic changes caused by environmental exposures may not always lead to impairments but may allow the organisms to achieve positive developmental outcomes through appropriate adaptation and a buffering response. Thus, some epigenetic adaptive responses to an immediate stimulus or exposure early in life would be expected to have a survival advantage but these same responses may also result in adverse developmental outcomes as they persist into later life stages. Although accumulating literature has identified environmentally induced epigenetic changes and linked them to health outcomes, we currently face challenges in the interpretation of the functional impact of their epigenetic plasticity. Summary Current environmental epigenetic research suggests that epigenetic processes may serve as a mechanism for resilience, and that they can be considered in terms of their impact on toxicity as a negative outcome, but also on adaptation for improved survival or health. This review encourages epigenetic environmental studies to move deeper into the functional meaning of epigenetic plasticity in development.

Obesity in pregnancy-Long-term effects on offspring hypothalamic-pituitary-adrenal axis and associations with placental cortisol metabolism: A systematic review

Article

Nov 2023
EUR J NEUROSCI

Obesity, affecting one in three pregnant women worldwide, is not only a major obstetric risk factor. The resulting low‐grade inflammation may have a long‐term impact on the offspring's HPA axis through dysregulation of maternal, placental and fetal corticosteroid metabolism, and children born of obese mothers have increased risk of diabetes and cardiovascular disease. The long‐term effects of maternal obesity on offspring neurodevelopment are, however, undetermined and could depend on the specific effects on placental and fetal cortisol metabolism. This systematic review evaluates how maternal obesity affects placental cortisol metabolism and the offspring's HPA axis. Pubmed, Embase and Scopus were searched for original studies on maternal BMI, obesity, and cortisol metabolism and transfer. Fifteen studies were included after the screening of 4556 identified records. Studies were small with heterogeneous exposures and outcomes. Two studies found that maternal obesity reduced placental HSD11β2 activity. In one study, umbilical cord blood cortisol levels were affected by maternal BMI. In three studies, an altered cortisol response was consistently seen among offspring in childhood ( n = 2) or adulthood ( n = 1). Maternal BMI was not associated with placental HSD11β1 or HSD11β2 mRNA expression, or placental HSD11β2 methylation. In conclusion, high maternal BMI is associated with reduced placental HSD11β2 activity and a dampened cortisol level among offspring, but the data is sparse. Further investigations are needed to clarify whether the HPA axis is affected by prenatal factors including maternal obesity and investigate if adverse effects can be ameliorated by optimising the intrauterine environment.

Fetal cardiovascular MRI

Chapter

Oct 2023

Maternofetal exposure to glicocorticoids and attention deficit hyperactivity disorder

Article

Jun 2023

Pregnancy is a critical development period, in a way that small alterations can be crucial in shaping an individual's health for the rest of his life. Depending on wich adversive conditions the fetus is exposed to, like metabolic, hormonal and nutricional alterations by the mother, there is a higher susceptibility in developing certain diseases, syndromes and disturbs. Among the aforementioned adversities, we can mention the excessive use of synthetic glucocorticoids during pregnancy. It is known that glucocorticoids act at various levels within the fetal brain, physiologically modulating the individual's neurological function, and, by that, exposing him to cognitive decline and behavioral changes. This review aimed to explore some evidence of the impact of excessive glucocorticoid signaling on HPA axis modulation and consequent fetal adaptive changes, related to the vulnerability of the development of Attention Deficit Hyperactivity Disorder (ADHD). In view of the growing number of diagnoses of this disease, it is necessary to review medical recommendations, the use of these drugs by pregnant women and infants, and public health policies.

Role of placenta in developmental programming of sex-specific adult outcomes

Chapter

Jan 2023

Kirtan Kaur

Impaired in vivo feto-placental development is associated with neonatal neurobehavioral outcomes

Article

Nov 2022

Background: Fetal growth restriction (FGR) is a risk factor for neurodevelopmental problems, yet remains poorly understood. We sought to examine the relationship between intrauterine development and neonatal neurobehavior in pregnancies diagnosed with antenatal FGR. Methods: We recruited women with singleton pregnancies diagnosed with FGR and measured placental and fetal brain volumes using MRI. NICU Network Neurobehavioral Scale (NNNS) assessments were performed at term equivalent age. Associations between intrauterine volumes and neurobehavioral outcomes were assessed using generalized estimating equation models. Results: We enrolled 44 women diagnosed with FGR who underwent fetal MRI and 28 infants underwent NNNS assessments. Placental volumes were associated with increased self-regulation and decreased excitability; total brain, brainstem, cortical and subcortical gray matter (SCGM) volumes were positively associated with higher self-regulation; SCGM also was positively associated with higher quality of movement; increasing cerebellar volumes were positively associated with attention, decreased lethargy, non-optimal reflexes and need for special handling; brainstem volumes also were associated with decreased lethargy and non-optimal reflexes; cerebral and cortical white matter volumes were positively associated with hypotonicity. Conclusion: Disrupted intrauterine growth in pregnancies complicated by antenatally diagnosed FGR is associated with altered neonatal neurobehavior. Further work to determine long-term neurodevelopmental impacts is warranted. Impact: Fetal growth restriction is a risk factor for adverse neurodevelopment, but remains difficult to accurately identify. Intrauterine brain volumes are associated with infant neurobehavior. The antenatal diagnosis of fetal growth restriction is a risk factor for abnormal infant neurobehavior.

The placenta epigenome–brain axis: placental epigenomic and transcriptomic responses that preprogram cognitive impairment

Article

Sep 2022

Aim: The placenta–brain axis reflects a developmental linkage where disrupted placental function is associated with impaired neurodevelopment later in life. Placental gene expression and the expression of epigenetic modifiers such as miRNAs may be tied to these impairments and are understudied. Materials & methods: The expression levels of mRNAs (n = 37,268) and their targeting miRNAs (n = 2083) were assessed within placentas collected from the ELGAN study cohort (n = 386). The ELGAN adolescents were assessed for neurocognitive function at age 10 and the association with placental mRNA/miRNAs was determined. Results: Placental mRNAs related to inflammatory and apoptotic processes are under miRNA control and associated with cognitive impairment at age 10. Conclusion: Findings highlight key placenta epigenome–brain relationships that support the developmental origins of health and disease hypothesis.

Human placental microRNAs dysregulated by cadmium exposure predict neurobehavioral outcomes at birth

Article

Jul 2022

Background: Prenatal cadmium (Cd) exposure has been implicated in both placental toxicity and adverse neurobehavioral outcomes. Placental microRNAs (miRNAs) may function to developmentally program adverse pregnancy and newborn health outcomes in response to gestational Cd exposure. Methods: In a subset of the Rhode Island Child Health Study (RICHS, n = 115) and the New Hampshire Birth Cohort Study (NHBCS, = 281), we used small RNA sequencing and trace metal analysis to identify Cd-associated expression of placental miRNAs using negative binomial generalized linear models. We predicted mRNAs targeted by Cd-associated miRNAs and relate them to neurobehavioral outcomes at birth through the integration of transcriptomic data and summary scores from the NICU Network Neurobehavioral Scale (NNNS). Results: Placental Cd concentrations are significantly associated with the expression level of five placental miRNAs in NHBCS, with similar effect sizes in RICHS. These miRNA target genes overrepresented in nervous system development, and their expression is correlated with NNNS metrics suggestive of atypical neurobehavioral outcomes at birth. Conclusions: Gestational Cd exposure is associated with the expression of placental miRNAs. Predicted targets of these miRNAs are involved in nervous system development and may also regulate placental physiology, allowing their dysregulation to modify developmental programming of early life health outcomes. Impact: This research aims to address the poor understanding of the molecular mechanisms governing adverse pregnancy and newborn health outcomes in response to Gestational cadmium (Cd) exposure. Our results outline a robust relationship between Cd-associated placental microRNA expression and NICU Network Neurobehavioral Scales (NNNS) at birth indicative of atypical neurobehavior. This study utilized healthy mother-infant cohorts to describe the role of Cd-associated dysregulation of placental microRNAs as a potential mechanism by which adverse neurobehavioral outcomes are developmentally programmed.

Residential green space in association with the methylation status in a CpG site within the promoter region of the placental serotonin receptor HTR2A

Article

Jun 2022

Green space could influence adult cognition and childhood neurodevelopment , and is hypothesized to be partly driven by epigenetic modifications. However, it remains unknown whether some of these associations are already evident during foetal development. Similar biological signals shape the developmental processes in the foetal brain and placenta.Therefore, we hypothesize that green space can modify epigenetic processes of cognition-related pathways in placental tissue, such as DNA-methylation of the serotonin receptor HTR2A. HTR2A-methylation was determined within 327 placentas from the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort using bisulphite-PCR-pyrosequencing. Total green space exposure was calculated using high-resolution land cover data derived from the Green Map of Flanders in seven buffers (50 m-3 km) and stratified into low (<3 m) and high (≥3 m) vegetation. Residential nature was calculated using the Land use Map of Flanders. We performed multivariate regression models adjusted for several a priori chosen covariables. For an IQR increment in total green space within a 1,000 m, 2,000 m and 3,000 m buffer the methylation of HTR2A increased with 1.47% (95%CI:0.17;2.78), 1.52% (95%CI:0.21;2.83) and 1.42% (95%CI:0.15;2.69), respectively. Additionally,, we found 3.00% (95%CI:1.09;4.91) and 1.98% (95%CI:0.28;3.68) higher HTR2A-methylation when comparing residences with and without the presence of nature in a 50 m and 100 m buffer, respectively. The methylation status of HTR2A in placental tissue is positively associated with maternal green space exposure. Future research is needed to understand better how these epigenetic changes are related to functional modifications in the placenta and the consequent implications for foetal development.

The Emergence of Developmental Behavioral Epigenomics

Article

Mar 2022

Association between placental toxic metal exposure and NICU Network Neurobehavioral Scales (NNNS) profiles in the Rhode Island Child Health Study (RICHS)

Article

Aug 2021
ENVIRON RES

Background – Prenatal exposure to heavy metals has been linked to a variety of adverse outcomes in newborn health and later life. Toxic metals such as cadmium (Cd), manganese (Mn) and lead (Pb) have been implicated to negatively affect newborn neurobehavior. Placental levels of these metals may provide additional understandings on the link between prenatal toxic metal exposures and neurobehavioral performances in newborns. Objective – To evaluate associations between placental concentrations of toxic metals and newborn neurobehavioral performance indicated through the NICU Network Neurobehavioral Scales (NNNS) latent profiles. Method – In the Rhode Island Child Health Study cohort (n = 625), newborn neurobehavioral performance was assessed with NNNS, and a latent profile analysis was used to define five discrete neurobehavioral profiles based on summary scales. Using multinomial logistic regression, we determined whether increased levels of placental toxic metals Cd, Mn and Pb associated with newborns assigned to the profile demonstrating atypical neurobehavioral performances. Results – Every doubling in placenta Cd concentration was associated with increased odds of newborns belonging to the atypical neurobehavior profile (OR: 2.72, 95% CI [1.09, 6.79]). Detectable placental Pb also demonstrated an increased odds of newborns assignment to the atypical profile (OR: 3.71, 95% CI [0.97, 13.96]) compared to being in the typical neurobehavioral profile. Conclusions – Toxic metals Cd and Pb measured in placental tissue may adversely impact newborn neurobehavior. Utilizing the placenta as a prenatal toxic metal exposure biomarker is useful in elucidating the associated impacts of toxic metals on newborn health.

Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Methyl Metabolism and in Sex‐Specific Placental Transcription Changes

Article

May 2021

Scope : Many pregnant women have higher folic acid (FA) intake due to food fortification and increased vitamin use. We reported that diets containing 5-fold higher FA than recommended for mice (5xFASD) during pregnancy, resulted in methylenetetrahydrofolate reductase (MTHFR) deficiency and altered choline/methyl metabolism, with neurobehavioral abnormalities in newborns. Our goal was to determine whether these changes had their origins in the placenta during embryonic development. Methods and results Female mice were fed control diet (CD) or 5xFASD for a month before mating and maintained on these diets until embryonic day 17.5. 5xFASD led to pseudo-MTHFR deficiency in maternal liver and altered choline/methyl metabolites in maternal plasma (increased methyltetrahydrofolate and decreased betaine). Methylation potential (S-adenosylmethionine: S-adenosylhomocysteine ratio) and glycerophosphocholine were decreased in placenta and embryonic liver. FASD resulted in sex-specific transcriptome profiles in placenta, with validation of dietary expression changes of 29 genes involved in angiogenesis, receptor biology or neurodevelopment, and altered methylation of the serotonin receptor 2A gene. Conclusion Moderate increases in folate intake during pregnancy result in placental metabolic and gene expression changes, particularly in angiogenesis, which may contribute to abnormal behavior in pups. These results are relevant for determining a safe upper limit for folate intake during pregnancy. This article is protected by copyright. All rights reserved

Strengths and challenges of longitudinal non-human primate neuroimaging

Article

Full-text available

Mar 2021

Longitudinal non-human primate neuroimaging has the potential to greatly enhance our understanding of primate brain structure and function. Here we describe its specific strengths, compared to both cross-sectional non-human primate neuroimaging and longitudinal human neuroimaging, but also its associated challenges. We elaborate on factors guiding the use of different analytical tools, subject-specific versus age-specific templates for analyses, and issues related to statistical power.

Placenta and Cord Blood as Source of Immune Markers of Offspring Neurodevelopment and Psychopathology

Chapter

Apr 2020

Classically, the placenta is considered the interface between the fetus and the mother. Furthermore, it is also a major transient endocrine organ that plays a key role in the interactions between the mother and the fetus during the pregnancy. The placenta also supports fetal development by means of adaptive responses to the maternal environment and protection against environmental insults. The prenatal environment has been increasingly implicated in general health outcomes during the lifespan, especially regarding the outcomes on neurodevelopment and mental health. There is strong evidence that the placenta and cord blood may be biological sources of several biomarkers of offspring neurodevelopment and psychopathology, both in animal and human studies. These biomarkers influence in utero development and, as a consequence, the later occurrence of abnormal neurodevelopment and psychopathology in the offspring. In this chapter, we discuss the role of placenta and cord blood as sources of immune markers and the potential pathways related to neurodevelopment and psychiatric diseases later in life.

Cytokine Model of Cognition in Relation to Mental Disorders During Neurodevelopment

Chapter

Apr 2020

Cognitive dysfunctions are current across psychiatric disorders and negatively impair patients’ quality of life and normal daily functioning and reduce clinical recovery. It is therefore important to understand the biological mechanisms underlying these cognitive impairments in order to develop new therapeutic strategies targeting these symptoms. Previous findings provided evidence for a cytokine model of cognition, in which immune cells and inflammatory cytokines can regulate cognitive processes in both physiological conditions and psychiatric disorders. There is now mounting evidence that genetic markers and perinatal environmental stressors contribute to abnormal development of both the immune system and the central nervous system and increase vulnerability to psychiatric disorders. However, whether cognitive alterations in psychiatric patients may also be a consequence of immune system dysregulations during development remains unclear. Hence, we review in this chapter the current knowledge suggesting that cognitive function in adult psychiatric patients may be influenced by long-lasting effect of immune system alterations during neurodevelopment. A better understanding of the complex influence of the developing immune system on brain structure and function may therefore help in identifying vulnerable individuals and develop preventive and therapeutic strategies to reduce the detrimental impact of cognitive impairments on psychiatric patients.

Influence of prenatal transportation stress-induced differential DNA methylation on the physiological control of behavior and stress response in suckling Brahman bull calves

Article

Full-text available

Dec 2019

The objective of this experiment was to examine potential differential methylation of DNA as a mechanism for altered behavioral and stress responses in prenatally stressed (PNS) compared with non-prenatally stressed (Control) young bull calves. Mature Brahman cows (n = 48) were transported for 2-h periods at 60 ± 5, 80 ± 5, 100 ± 5, 120 ± 5, and 140 ± 5 d of gestation (Transported group) or maintained as non-transported Controls (n = 48). From the offspring born to Transported and Control cows, a subset of 28-d-old intact bulls (n = 7 PNS; n = 7 Control) were evaluated for methylation of DNA of behavior and stress response associated genes. Methylation of DNA from white blood cells was assessed via reduced representation bisulfite sequencing methods. Because increased methylation of DNA within gene promoter regions has been associated with decreased transcriptional activity of the corresponding gene, differentially methylated (P ≤ 0.05) CG sites (cytosine followed by a guanine nucleotide) located within promoter regions (n = 1,205) were used to predict (using Ingenuity Pathway Analysis software) alterations to canonical pathways in PNS compared with Control bull calves. Among differentially methylated genes (P ≤ 0.05) related to behavior and the stress response were OPRK1, OPRM1, PENK, POMC, NR3C2, TH, DRD1, DRD5, COMT, HTR6, HTR5A, GABRA4, GABRQ, and GAD2. Among altered (P < 0.05) signaling pathways related to behavior and the stress response were Opioid Signaling, Corticotropin-Releasing Hormone Signaling, Dopamine Receptor Signaling, Dopamine-DARPP32 Feedback in cAMP Signaling, Serotonin Receptor Signaling, and GABA Receptor Signaling. Alterations to behavior and stress response-related genes and canonical pathways supported previously observed elevations in temperament score and serum cortisol through weaning in the larger population of PNS calves from which bulls in this study were derived. Differential methylation of DNA and predicted alterations to behavior and stress response-related pathways in PNS compared with Control bull calves suggest epigenetic programming of behavior and the stress response in utero.

Epigenetic perpetuation of the impact of early life stress on behavior

Article

Aug 2019

There is growing support for epigenetic perpetuation of early life stressful experiences on offspring behavior. Evidence primarily exists for maternal psychosocial experiences (i.e. mood and exposure to stress, adversity, or trauma) to associate with epigenetic modification to offspring genes involved in neurobehavioral pathways (i.e. glucocorticoid, oxytocin, and serotonin system genes). Such epigenetic modifications associate with altered infant neurobehavioral developmental profiles, stress reactivity, and maladaptive behaviors observed in childhood and/or adolescence. Epigenetic transmission of adverse early life experiences to the offspring genome most often occurs during the prenatal and early postnatal periods, when developing systems are more sensitive to environmental signals. Emerging work suggests interventions that foster positive maternal–infant interactions may attenuate the epigenetic impact of early life stress.

The Placenta in Neonatal Encephalopathy: A Case–Control Study

Article

Jun 2018
J Pediatr

Objective: We assessed whether specific histologic placental lesions were associated with risk for neonatal encephalopathy, a strong predictor of death or cerebral palsy. Study design: Case–control study of singletons with gestational ages ≥35 weeks. Data were abstracted from a prospectively collected database of consecutive births at a hospital in which placental samples from specified sites are collected and stored for all inborn infants. Placentas of infants with neonatal encephalopathy were compared with randomly selected control infants (ratio of 1:3). Placental histologic slides were read by a single experienced perinatal pathologist unaware of case status, using internationally recommended definitions and terminology. Findings were grouped into inflammatory, maternal, or fetal vascular malperfusion (FVM) and other lesions. Results: Placental samples were available for 73 of 87 (84%) cases and 253 of 261 (97%) controls. Delivery complications and gross placental abnormalities were more common in cases, of whom 4 died. Inflammation and maternal vascular malperfusion did not differ, and findings consistent with global FVM were more frequent in case (20%) than control (7%) placentas (P =.001). There was a trend toward more segmental FVM and high-grade FVM (fetal thrombotic vasculopathy) among cases. Some type of FVM was observed in 24% of placentas with neonatal encephalopathy. In infants with both neonatal encephalopathy and placental FVM, more often than in infants with neonatal encephalopathy without FVM, electronic fetal monitoring tracings were considered possibly or definitely abnormal (P =.028). Conclusions: Vascular malperfusion of subacute or chronic origin on the fetal side of the placenta was associated with increased risk of neonatal encephalopathy.

Prenatal Major Depressive Disorder, Placenta Glucocorticoid and Serotonergic Signaling, and Infant Cortisol Response

Article

Full-text available

Oct 2016

Objectives: Extending prior studies of prenatal adversity and depressive symptoms, we tested associations between maternal prenatal major depressive disorder (MDD) and infant cortisol regulation. Based on prior findings by our group, we also tested placenta glucocorticoid (HSD11B2 methylation) and serotonin (SLC6A4 gene expression) signaling as moderators of links between prenatal MDD and infant cortisol. Methods: Participants were 153 mother-infant pairs from a low-income, diverse sample (M [SD] age = 26[6] years). Repeated structured diagnostic interviews were used to identify mothers with (a) prenatal MDD, (b) preconception-only MDD, and (c) controls. Placenta samples were assayed for HSD11B2 methylation and SLC6A4 gene expression. Infant salivary cortisol response to a neurobehavioral examination was assessed at 1 month. Results: Daughters of prenatal MDD mothers had 51% higher baseline (ratio = 1.51; 95% confidence interval [CI] = 1.01-2.27; p = .045) and 64% higher stress responsive cortisol (ratio = 1.64; 95% CI = 1.05-2.56; p = .03) than daughters of controls and 75% higher stress-responsive cortisol (ratio = 1.75; 95% CI = 1.04-2.94; p = .04) than daughters of preconception-only MDD mothers. HSD11B2 methylation moderated links between prenatal MDD and baseline cortisol (p = .02), with 1% methylation decreases associated with 9% increased baseline cortisol in infants of prenatal MDD mothers (ratio = 1.09; 95% CI = 1.01-1.16). SLC6A4 expression moderated links between prenatal MDD and cortisol response among boys alone (p = .007), with 10-fold increases in expression associated with threefold increases in stress-responsive cortisol (ratio = 2.87; 95% CI = 1.39-5.93) in sons of control mothers. Conclusions: Results highlight specificity of associations between prenatal versus preconception MDD and cortisol regulation and the importance and complexity of placenta glucocorticoid and serotonergic pathways underlying the intergenerational transmission of risk from maternal adversity.

Methylation of the Glucocorticoid Receptor (NR3C1) in Placenta Is Associated with Infant Cry Acoustics

Article

Full-text available

Jun 2016

Epigenetic mechanisms regulating expression of the glucocorticoid receptor gene (NR3C1) promoter may influence behavioral and biological aspects of stress response in human infants. Acoustic features of infant crying are an indicator of neurobehavioral and neurological status not yet investigated in relation to epigenetic mechanisms. We examined NR3C1 methylation in placental tissue from a series of 120 healthy newborn infants in relation to a detailed set of acoustic features extracted from newborn infant cries. We identified significant associations of NR3C1 methylation with energy variation in infants’ cries as well as with the presence of very high fundamental frequency in cry utterances. The presence of high fundamental frequency in cry (above 1 kHz) has been linked to poor vocal tract control, poor regulation of stress response, and may be an indicator of poor neurobehavioral integrity. Thus, these results add to evidence linking epigenetic alteration of the NR3C1 gene in the placenta to neurodevelopmental features in infants.

Epigenetic Regulation of Placental NR3C1 : Mechanism Underlying Prenatal Programming of Infant Neurobehavior by Maternal Smoking?

Article

Full-text available

Feb 2016
CHILD DEV

Epigenetic regulation of the placental glucocorticoid receptor gene (NR3C1) was investigated as a mechanism underlying links between maternal smoking during pregnancy (MSDP) and infant neurobehavior in 45 mother–infant pairs (49% MSDP-exposed; 52% minorities; ages 18–35). The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale was administered 7 times over the 1st postnatal month; methylation of placental NR3C1 was assessed via bisulfite pyrosequencing. Increased placental NR3C1 methylation was associated with increased infant attention and self-regulation, and decreased lethargy and need for examiner soothing over the 1st postnatal month. A causal steps approach revealed that NR3C1 methylation and MSDP were independently associated with lethargic behavior. Although preliminary, results highlight the importance of epigenetic mechanisms in elucidating pathways to neurobehavioral alterations from MSDP.

Neurobehavior Related to Epigenetic Differences in Preterm Infants

Article

Full-text available

Nov 2015

Aim: Determine if methylation of HSD11B2 and NR3C1 is associated with neurobehavioral profiles in preterm infants. Patients & methods: Neurobehavior was measured before discharge from the hospital in 67 preterm infants. Cheek swabs were collected for DNA extraction. Results: Infants with the high-risk neurobehavioral profile showed more methylation than infants with the low-risk neurobehavioral profile at CpG3 for NR3C1 and less methylation of CpG3 for HSD11B2. Infants with these profiles were more likely to have increased methylation of NR3C1 and decreased methylation of HSD11B2 at these CpG sites. Conclusion: Preterm birth is associated with epigenetic differences in genes that regulate cortisol levels related to high-risk neurobehavioral profiles.

Expression of imprinted genes in placenta is associated with infant neurobehavioral development

Article

Full-text available

Jul 2015
EPIGENETICS

Genomic imprinting disorders often exhibit delayed neurobehavioral development, suggesting this unique mechanism of epigenetic regulation plays a role in mental and neurological health. While major errors in imprinting have been linked to adverse health outcomes, there has been little research conducted on how moderate variability in imprinted gene expression within a population contributes to differences in neurobehavioral outcomes, particularly at birth. Here, we profiled the expression of 108 known and putative imprinted genes in human placenta samples from 615 infants assessed by the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). Data reduction identified ten genes (DLX5, DHCR24, VTRNA2-1, PHLDA2, NPAP1, FAM50B, GNAS-AS1, PAX8-AS1, SHANK2, and COPG2IT1) whose expression could distinguish between newborn neurobehavioral profiles derived from the NNNS. Clustering infants based on the expression pattern of these genes identified 2 groups of infants characterized by reduced quality of movement, increased signs of asymmetrical and non-optimal reflexes, and increased odds of demonstrating increased signs of physiologic stress and abstinence. Overall, these results suggest that common variation in placental imprinted gene expression is linked to suboptimal performance on scales of neurological functioning as well as with increased signs of physiologic stress, highlighting the central importance of the control of expression of these genes in the placenta for neurobehavioral development.

Prenatal predictors of infant self-regulation: The contributions of placental DNA methylation of NR3C1 and neuroendocrine activity

Article

Full-text available

May 2015

We examined whether placental DNA methylation of the glucocorticoid receptor gene, NR3C1 was associated with self-regulation and neuroendocrine responses to a social stressor in infancy. Placenta samples were obtained at birth and mothers and their infants (n = 128) participated in the still-face paradigm when infants were 5 months old. Infant self-regulation following the still-face episode was coded and pre-stress cortisol and cortisol reactivity was assessed in response to the still-face paradigm. A factor analysis of NR3C1 CpG sites revealed two factors: one for CpG sites 1-4 and the other for sites 5-13. DNA methylation of the factor comprising NR3C1 CpG sites 5-13 was related to greater cortisol reactivity and infant self-regulation, but cortisol reactivity was not associated with infant self-regulation. The results reveal that prenatal epigenetic processes may explain part of the development of infant self-regulation.

Acoustic measures of the cry characteristics of healthy newborns and newborns with pathologies

Article

Full-text available

Jan 2013

Several hypotheses have been formulated as a result of observing spectrograms of the audio signals of the newborn infant cry in numerous studies. Our study is based on a few of these hypotheses. The purpose of this article is to differentiate pathological crying from healthy crying through acoustic cry analysis based on neurophysiological parameters of newborns. The automatic estimation of the characteristics of relevant cry signals, such as phonation, hyperphonation, and dysphonation, expressed as percentages, as well as unvoiced sound and mode change percentages, have enabled us to distinguish among the pathologies selected for this study. The results obtained have helped us to make quantitative associations between cry characteristics and pathological conditions affecting newborns.

Prospective Evaluation of Associations Between Prenatal Cortisol and Adulthood Coronary Heart Disease Risk: The New England Family Study

Article

Full-text available

Mar 2015

Increasing evidence suggests that early life factors may influence coronary heart disease (CHD) risk; however, little is known about the contributions of prenatal cortisol. Objectives were to prospectively assess the associations of maternal cortisol levels during pregnancy with offspring's 10-year CHD risk during middle age. Participants were 262 mother-offspring dyads from the New England Family Study. Maternal free cortisol was assessed in third-trimester maternal serum samples. Ten-year CHD risk was calculated in offspring at a mean age of 42 years, using the validated Framingham risk algorithm incorporating diabetes, systolic and diastolic blood pressure, total and high-density lipoprotein cholesterol, smoking, age, and sex. In multivariable-adjusted linear regression analyses adjusted for age and race/ethnicity, high versus low maternal cortisol tertile was associated with 36.7% (95% confidence interval [CI] = 8.4% to 72.5%) greater mean 10-year CHD risk score in women. There was no association in men (-2.8%, 95% CI = -23.8% to 24.0%). Further adjustment for in utero socioeconomic position showed 26.1% (95% CI = -0.5% to 59.9%) greater CHD risk in women. Adjustment for maternal age and size for gestational age had little effect on findings. Maternal prenatal cortisol levels were positively associated with 10-year CHD risk among female, and not male, offspring. Adjusting for socioeconomic position during pregnancy reduced effect size in women, suggesting that it may be a common prior factor in both maternal cortisol and CHD risk. These findings provide evidence that targeting mothers who have elevated prenatal cortisol levels, including elevated cortisol in the setting of low socioeconomic position, may potentially reduce long-term CHD risk in their offspring.

Placental DNA Methylation Related to Both Infant Toenail Mercury and Adverse Neurobehavioral Outcomes

Article

Full-text available

Mar 2015
ENVIRON HEALTH PERSP

Prenatal mercury (Hg) exposure is associated with adverse child neurobehavioral outcomes. As Hg can interfere with placental functioning, and cross the placenta to target fetal brain, prenatal Hg exposure can negatively impact fetal growth and development directly and indirectly. To examine potential associations between prenatal Hg exposure assessed through infant toenail Hg, placental DNA methylation changes, and newborn neurobehavioral outcomes. The methylation status of >485,000 CpG loci was interrogated in 192 placental samples using Illumina's Infinium HumanMethylation450 BeadArray. Hg concentrations were analyzed in toenail clippings from a subset of 41 infants; neurobehavior was assessed using the NICU Network Neurobehavioral Scales (NNNS) in an independent subset of 151 infants. 339 loci were identified with an average methylation difference >0.125 between any two toenail Hg tertiles. Variation amongst these loci was subsequently found to be associated with a high-risk neurodevelopmental profile (omnibus p-value=0.007) characterized by the NNNS. Ten loci had p<0.01 for the association between methylation and the high-risk NNNS profile. Six of ten loci reside in the EMID2 gene and were hypomethylated in the 16 high-risk profile infants' placentas. Methylation at these loci was moderately correlated (correlation coefficients range -0.33 to -0.45) with EMID2 expression. EMID2 hypomethylation may represent a novel mechanism linking in utero Hg exposure and adverse infant neurobehavioral outcomes.

Placental FKBP5 Genetic and Epigenetic Variation Is Associated with Infant Neurobehavioral Outcomes in the RICHS Cohort

Article

Full-text available

Aug 2014
PLOS ONE

Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negative regulator of cortisol response, FKBP5 methylation has been linked to brain morphology and mental disorder risk, and genetic variation of FKBP5 was associated with post-traumatic stress disorder in adults. We hypothesized that placental FKBP5 methylation and genetic variation contribute to gene expression control, and are associated with infant neurodevelopmental outcomes assessed using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). In 509 infants enrolled in the Rhode Island Child Health Study, placental FKBP5 methylation was measured at intron 7 using quantitative bisulfite pyrosequencing. Placental FKBP5 mRNA was measured in a subset of 61 infants by quantitative PCR, and the SNP rs1360780 was genotyped using a quantitative allelic discrimination assay. Relationships between methylation, expression and NNNS scores were examined using linear models adjusted for confounding variables, then logistic models were created to determine the influence of methylation on membership in high risk groups of infants. FKBP5 methylation was negatively associated with expression (P = 0.08, r = -0.22); infants with the TT genotype had higher expression than individuals with CC and CT genotypes (P = 0.06), and those with CC genotype displayed a negative relationship between methylation and expression (P = 0.06, r = -0.43). Infants in the highest quartile of FKBP5 methylation had increased risk of NNNS high arousal compared to infants in the lowest quartile (OR 2.22, CI 1.07-4.61). TT genotype infants had increased odds of high NNNS stress abstinence (OR 1.98, CI 0.92-4.26). Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta's ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.

Associations Between Early Life Stress and Gene Methylation in Children

Article

Full-text available

Jul 2014
CHILD DEV

Children exposed to extreme stress are at heightened risk for developing mental and physical disorders. However, little is known about mechanisms underlying these associations in humans. An emerging insight is that children's social environments change gene expression, which contributes to biological vulnerabilities for behavioral problems. Epigenetic changes in the glucocorticoid receptor gene, a critical component of stress regulation, were examined in whole blood from 56 children aged 11–14 years. Children exposed to physical maltreatment had greater methylation within exon 1F in the NR3C1 promoter region of the gene compared to nonmaltreated children, including the putative NGFI-A (nerve growth factor) binding site. These results highlight molecular mechanisms linking childhood stress with biological changes that may lead to mental and physical disorders.

Behavioral epigenetics and the developmental origins of child mental health disorders

Article

Full-text available

Dec 2012

Advances in understanding the molecular basis of behavior through epigenetic mechanisms could help explain the developmental origins of child mental health disorders. However, the application of epigenetic principles to the study of human behavior is a relatively new endeavor. In this paper we discuss the ‘Developmental Origins of Health and Disease’ including the role of fetal programming. We then review epigenetic principles related to fetal programming and the recent application of epigenetics to behavior. We focus on the neuroendocrine system and develop a simple heuristic stress-related model to illustrate how epigenetic changes in placental genes could predispose the infant to neurobehavioral profiles that interact with postnatal environmental factors potentially leading to mental health disorders. We then discuss from an ‘Evo-Devo’ perspective how some of these behaviors could also be adaptive. We suggest how elucidation of these mechanisms can help to better define risk and protective factors and populations at risk.

The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior

Article

Full-text available

Oct 2013
EPIGENETICS

Exposure to maternal mood disorders in utero may program infant neurobehavior via DNA methylation of the glucocorticoid receptor (NR3C1) and 11β-hydroxysteroid dehydrogenase type 2 ( 11β-HSD-2), two placental genes that have been implicated in perturbations of the hypothalamic pituitary adrenocortical (HPA) axis. We tested the relationship among prenatal exposure to maternal depression or anxiety, methylation of exon 1F of NR3C1 and 11β-HSD-2, and newborn neurobehavior. Controlling for relevant covariates, infants whose mothers were depressed during pregnancy and showed greater methylation of placental NR3C1 CpG2 had poorer self-regulation, more hypotonia, and more lethargy than infants whose mothers were not depressed. On the other hand, infants whose mothers were anxious during pregnancy and showed greater methylation of placental 11β-HSD-2 CpG4 were more hypotonic compared with infants of mothers who were not anxious during pregnancy. Our results support the fetal programming hypothesis and suggest that fetal adjustments to cues from the intrauterine environment, in this case an environment that could be characterized by increased exposure to maternal cortisol, may lead to poor neurodevelopmental outcomes.

Placental HTR2A methylation is associated with infant neurobehavioral outcomes

Article

Full-text available

Jun 2013
EPIGENETICS

The serotonin receptor, HTR2A, exhibits placental expression and function and can be controlled through DNA methylation. The relationship between methylation of HTR2A in the placenta and neurodevelopmental outcomes, evaluated using the NICU Network Neurobehavioral Scales (NNNS), was assessed in newborn infants (n = 444). HTR2A methylation was significantly higher in males and marginally higher in infants whose mothers reported tobacco use during pregnancy. Controlling for confounding variables, HTR2A methylation was negatively associated with infant quality of movement (p = 0.05) and positively associated with infant attention (p = 0.0001). These results suggest that methylation of the HTR2A gene can be biologically and environmentally modulated and is associated with key measures of neurodevelopment.

Placental miRNA Expression Profiles Associated with Measures of Infant Neurobehavioral Outcomes

Article

Full-text available

Jun 2013
Pediatr Res

Background: A growing body of research suggests that the intrauterine environment influences fetal neurodevelopment by altering the functional placental epigenome. A number of microRNAs (miRNAs) are expressed in the placenta, may be sensitive to dysregulation by environmental exposures, and are associated with adverse pregnancy outcomes. Our study aimed to identify the relationships between placental miRNA expression and newborn neurobehavior. Methods: We examined the association between the expression of miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182 in total RNA from the placentas of 86 term infants as measured by quantitative real-time PCR and newborn neurobehavioral outcomes as assessed using the NICU Network Neurobehavioral Scales (NNNS). Results: Bivariate analysis revealed that placental miR-16 expression is negatively associated with attention score (P = 0.006), whereas expressions of both miR-146a and miR-182 are positively associated with quality of movement score (P = 0.016 and P = 0.016, respectively). Controlling for potential confounders, high miR-16 expression is significantly associated with reduced attention score (P = 0.04), and high miR-146a and miR-182 expressions are significantly associated with increased quality of movement score (P = 0.04 and P = 0.01, respectively). Conclusion: These results suggest that placental miRNA expression is associated with early neurobehavioral outcomes and miRNAs in the placenta may contribute to the developmental origins of infant neurobehavior.

Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor

Article

Full-text available

Jul 2011

Prenatal exposure to maternal stress can have lifelong implications for psychological function, such as behavioral problems and even the development of mental illness. Previous research suggests that this is due to transgenerational epigenetic programming of genes operating in the hypothalamic-pituitary-adrenal axis, such as the glucocorticoid receptor (GR). However, it is not known whether intrauterine exposure to maternal stress affects the epigenetic state of these genes beyond infancy. Here, we analyze the methylation status of the GR gene in mothers and their children, at 10-19 years after birth. We combine these data with a retrospective evaluation of maternal exposure to intimate partner violence (IPV). Methylation of the mother's GR gene was not affected by IPV. For the first time, we show that methylation status of the GR gene of adolescent children is influenced by their mother's experience of IPV during pregnancy. As these sustained epigenetic modifications are established in utero, we consider this to be a plausible mechanism by which prenatal stress may program adult psychosocial function.

Genetic and Epigenetic Variation of the Glucocorticoid Receptor (NR3C1) in Placenta and Infant Neurobehavior

Article

Full-text available

Jun 2012
DEV PSYCHOBIOL

The intrauterine environment can impact the developing infant by altering the function of the placenta through changes to the epigenetic regulatory features of this tissue. Genetic variation, too, may impact infant development or may modify the relationship between epigenetic alterations and infant outcomes. To examine the associations of these variations with early life infant neurodevelopment, we examined the extent of DNA methylation of the glucocorticoid receptor gene (NR3C1) promoter and a common single nucleotide polymorphism in the promoter region in a series of 186 placentas from healthy newborn infants. We associated these molecular features with specific summary measures from the NICU Network Neurobehavioral Scales. After controlling for genotype and confounders, we identified significant associations of NR3C1 methylation with infant quality of movement (p = .05) and with infant attention (p = .05), and a potential interaction between methylation and genotype on infant attention score. These results suggest that epigenetic alteration of the NR3C1 gene in the placentas of genetically susceptible infants can have impacts on neurodevelopment which may have lifelong impact on neurobehavioral and mental health outcomes. Further research is needed to more precisely define these relationships and the interaction between epigenetic alterations and genetic variations on infant health. © 2012 Wiley Periodicals, Inc. Dev Psychobiol.

Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems

Article

Full-text available

Apr 2012
P NATL ACAD SCI USA

Stress-related variation in the intrauterine milieu may impact brain development and emergent function, with long-term implications in terms of susceptibility for affective disorders. Studies in animals suggest limbic regions in the developing brain are particularly sensitive to exposure to the stress hormone cortisol. However, the nature, magnitude, and time course of these effects have not yet been adequately characterized in humans. A prospective, longitudinal study was conducted in 65 normal, healthy mother-child dyads to examine the association of maternal cortisol in early, mid-, and late gestation with subsequent measures at approximately 7 y age of child amygdala and hippocampus volume and affective problems. After accounting for the effects of potential confounding pre- and postnatal factors, higher maternal cortisol levels in earlier but not later gestation was associated with a larger right amygdala volume in girls (a 1 SD increase in cortisol was associated with a 6.4% increase in right amygdala volume), but not in boys. Moreover, higher maternal cortisol levels in early gestation was associated with more affective problems in girls, and this association was mediated, in part, by amygdala volume. No association between maternal cortisol in pregnancy and child hippocampus volume was observed in either sex. The current findings represent, to the best of our knowledge, the first report linking maternal stress hormone levels in human pregnancy with subsequent child amygdala volume and affect. The results underscore the importance of the intrauterine environment and suggest the origins of neuropsychiatric disorders may have their foundations early in life.

Placental 11-Beta Hydroxysteroid Dehydrogenase Methylation Is Associated with Newborn Growth and a Measure of Neurobehavioral Outcome

Article

Full-text available

Mar 2012
PLOS ONE

There is growing evidence that the intrauterine environment can impact the neurodevelopment of the fetus through alterations in the functional epigenome of the placenta. In the placenta, the HSD11B2 gene encoding the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol, is regulated by DNA methylation, and has been shown to be susceptible to stressors from the maternal environment. We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 185 healthy newborn infants and infant and maternal characteristics, as well as the association between this epigenetic variability and newborn neurobehavioral outcome assessed with the NICU Network Neurobehavioral Scales. Controlling for confounders, HSD11B2 methylation extent is greatest in infants with the lowest birthweights (P = 0.04), and this increasing methylation was associated with reduced scores of quality of movement (P = 0.04). These results suggest that factors in the intrauterine environment which contribute to birth outcome may be associated with placental methylation of the HSD11B2 gene and that this epigenetic alteration is in turn associated with a prospectively predictive early neurobehavioral outcome, suggesting in some part a mechanism for the developmental origins of infant neurological health.

Cottrell EC, Seckl JR. Prenatal stress, glucocorticoids and the programming of adult disease. Front Behav Neurosci 3: 19

Article

Full-text available

Sep 2009

Numerous clinical studies associate an adverse prenatal environment with the development of cardio-metabolic disorders and neuroendocrine dysfunction, as well as an increased risk of psychiatric diseases in later life. Experimentally, prenatal exposure to stress or excess glucocorticoids in a variety of animal models can malprogram offspring physiology, resulting in a reduction in birth weight and subsequently increasing the likelihood of disorders of cardiovascular function, glucose homeostasis, hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviours in adulthood. During fetal development, placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) provides a barrier to maternal glucocorticoids. Reduced placental 11beta-HSD2 in human pregnancy correlates with lower birth weight and higher blood pressure in later life. Similarly, in animal models, inhibition or knockout of placental 11beta-HSD2 lowers offspring birth weight, in part by reducing glucose delivery to the developing fetus in late gestation. Molecular mechanisms thought to underlie the programming effects of early life stress and glucocorticoids include epigenetic changes in target chromatin, notably affecting tissue-specific expression of the intracellular glucocorticoid receptor (GR). As such, excess glucocorticoids in early life can permanently alter tissue glucocorticoid signalling, effects which may have short-term adaptive benefits but increase the risk of later disease.

Aging and Environmental Exposures Alter Tissue-Specific DNA Methylation Dependent upon CpG Island Context

Article

Full-text available

Sep 2009
PLOS GENET

Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variations in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1,413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P

Prenatal Stress and Neurodevelopment of the Child: Focus on the HPA Axis and Role of the Placenta

Article

Full-text available

Feb 2009
DEV NEUROSCI-BASEL

Recent human studies have shown that a wide variety of prenatal stressors, from anxiety and partner relationship problems, to natural disasters, increase the risk for a diverse range of adverse neurodevelopmental outcomes in the child. These include impaired cognitive development and behavioral problems, autism and schizophrenia. However, many questions remain about the underlying processes. Much of the research, based on animal studies, has focussed on the maternal HPA axis, with mixed results. Maternal stress or anxiety during pregnancy has been found to be weakly associated with raised maternal cortisol, if at all. The placenta may be a more promising programming vector, because it controls fetal exposure to the maternal environment. Animal studies indicate that prenatal stress can affect the activity of the placental barrier enzyme 11-betaHSD2, which metabolises cortisol. We review the evidence for a similar mechanism in humans and how maternal stress may cause other changes in the placenta which affect fetal neurodevelopment.

Neuroscience, Molecular Biology, and the Childhood Roots of Health Disparities: Building a New Framework for Health Promotion and Disease Prevention

Article

Full-text available

Jul 2009
J Am Med Assoc

A scientific consensus is emerging that the origins of adult disease are often found among developmental and biological disruptions occurring during the early years of life. These early experiences can affect adult health in 2 ways--either by cumulative damage over time or by the biological embedding of adversities during sensitive developmental periods. In both cases, there can be a lag of many years, even decades, before early adverse experiences are expressed in the form of disease. From both basic research and policy perspectives, confronting the origins of disparities in physical and mental health early in life may produce greater effects than attempting to modify health-related behaviors or improve access to health care in adulthood.

Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse

Article

Full-text available

Apr 2009
NAT NEUROSCI

Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.

LOW weight gain in infancy and suicide in adult life

Article

Full-text available

Dec 1995

One theory suggests that depression in adult life originates through parental indifference, abuse, and other adverse influences in childhood. The possible contribution of development in infancy has received little attention.1 We therefore examined the association between infant growth and later suicide in 15500 men and women. Depression underlies 70% of deaths by suicide.2 As previously described, all births in Hertfordshire from 1911 onwards were notified by the attending midwife.3 Health visitors saw the babies periodically throughout infancy, recorded the method of feeding, and wrote general comments on the baby's development and well being. At 1 year the babies were weighed. We traced 10141 (79%) of the boys born during 1911-30 and 5585 (60%) of the girls born during 1923-30. The average birthweight and weight at 1 year of those who were traced were the same as those of the babies who were not traced. We compared the numbers of deaths from suicide at ages 20-74 …

Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308: 1466-1469

Article

Full-text available

Jul 2005
SCIENCE

Transgenerational effects of environmental toxins require either a chromosomal or epigenetic alteration in the germ line. Transient exposure of a gestating female rat during the period of gonadal sex determination to the endocrine disruptors vinclozolin (an antiandrogenic compound) or methoxychlor (an estrogenic compound) induced an adult phenotype in the F1 generation of decreased spermatogenic capacity (cell number and viability) and increased incidence of male infertility. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined (that is, F1 to F4). The effects on reproduction correlate with altered DNA methylation patterns in the germ line. The ability of an environmental factor (for example, endocrine disruptor) to reprogram the germ line and to promote a transgenerational disease state has significant implications for evolutionary biology and disease etiology.

Gunnar M, Quevedo K. The neurobiology of stress and development. Annu Rev Psychol 58: 145-173

Article

Full-text available

Feb 2007

Stress is a part of every life to varying degrees, but individuals differ in their stress vulnerability. Stress is usefully viewed from a biological perspective; accordingly, it involves activation of neurobiological systems that preserve viability through change or allostasis. Although they are necessary for survival, frequent neurobiological stress responses increase the risk of physical and mental health problems, perhaps particularly when experienced during periods of rapid brain development. Recently, advances in noninvasive measurement techniques have resulted in a burgeoning of human developmental stress research. Here we review the anatomy and physiology of stress responding, discuss the relevant animal literature, and briefly outline what is currently known about the psychobiology of stress in human development, the critical role of social regulation of stress neurobiology, and the importance of individual differences as a lens through which to approach questions about stress experiences during development and child outcomes.

Tissue specific glucocorticoid receptor expression, a role for alternative first exon usage?

Article

Full-text available

Dec 2006
BIOCHEM PHARMACOL

The CpG island upstream of the GR is highly structured and conserved at least in all the animal species that have been investigated. Sequence alignment of these CpG islands shows inter-species homology ranging from 64 to 99%. This 3.1kb CpG rich region upstream of the GR exon 2 encodes 5' untranslated mRNA regions. These CpG rich regions are organised into multiple first exons and, as we and others have postulated, each with its own promoter region. Alternative mRNA transcript variants are obtained by the splicing of these alternative first exons to a common acceptor site in the second exon of the GR. Exon 2 contains an in-frame stop codon immediately upstream of the ATG start codon to ensure that this 5' heterogeneity remains untranslated, and that the sequence and structure of the GR is unaffected. Tissue specific differential usage of exon 1s has been observed in a range of human tissues, and to a lesser extent in the rat and mouse. The GR expression level is tightly controlled within each tissue or cell type at baseline and upon stimulation. We suggest that no single promoter region may be capable of containing all the necessary promoter elements and yet preserve the necessary proximity to the transcription initiation site to produce such a plethora of responses. Thus we further suggest that alternative first exons each under the control of specific transcription factors control both the tissue specific GR expression and are involved in the tissue specific GR transcriptional response to stimulation. Spreading the necessary promoter elements over multiple promoter regions, each with an associated alternative transcription initiation site would appear to vastly increase the capacity for transcriptional control of GR.

A users guide to HPA axis research

Article

Nov 2016
PHYSIOL BEHAV

Regions of Variable DNA Methylation in Human Placenta Associated with Newborn Neurobehavior

Article

Jul 2016
EPIGENETICS

The placenta regulates the in utero environment and functionally impacts fetal development. Candidate gene studies identified variation in placental DNA methylation is associated with newborn neurologic and behavioral outcomes including movement quality, lethargic behavior, attention, and arousal. We sought to identify novel regions of variable DNA methylation associated with newborn attention, lethargy, quality of movement, and arousal by performing an epigenome-wide association study in 335 infants from a US birth cohort. Methylation status was quantified using the Illumina HumanMethylation450 BeadChip array and associations to newborn outcomes assessed by the NICU Network Neurobehavioral Scales (NNNS) were identified while incorporating established bioinformatics algorithms to control for confounding by cell type composition. Methylation of CpGs within FHIT (cg15970800) and ANKRD11 (cg16710656) demonstrated genome-wide significance (P<1.8×10(-7)) in specific associations with infant attention. CpGs whose differential methylation was associated with all four neurobehavioral outcomes were common to 50 genes involved in biological processes relating to cellular adhesion and nervous system development. Comprehensive methylation profiling identified relationships between methylation of FHIT and ANKRD11, which have been previously linked to neurodevelopment and behavioral outcomes in genetic association studies. Subtle changes in DNA methylation of these genes within the placenta may impact normal variation of a newborn's ability to alter and track visual and sound stimuli. Gene ontology analysis suggested that those genes with variable methylation related to these outcomes are over-represented in biological pathways involved in brain development and placental physiology, supportive of our hypothesis for a key role of the placenta in neurobehavioral outcomes.

Examining the joint contribution of placental NR3C1 and HSD11B2 methylation for infant neurobehavior

Article

Nov 2014

Infant neurobehavior, a potential sentinel of future mental and behavioral morbidity characterized in part by reflex symmetry, excitability and habituation to stimuli, is influenced by aspects of the intrauterine environment partially through epigenetic alterations of genes involved in the stress response. DNA methylation of two related cortisol response genes, the glucocorticoid receptor (NR3C1), a nuclear receptor to which cortisol binds, and 11-beta hydroxysteroid dehydrogenase (HSD11B2), the enzyme responsible for conversion of cortisol into inactive cortisone, independently associate with infant neurobehavior. Although these factors are part of a common cortisol regulation pathway, the combined effect of DNA methylation of these factors on infant neurobehavior has not been characterized. Therefore, we conducted an examination of the joint contribution of NR3C1 and HSD11B2 DNA methylation on infant neurobehavior. Among 372 healthy term newborns, we tested the interaction between placental NR3C1 and HSD11B2 DNA methylation in association with neurobehavior as assessed with the validated NICU Network Neurobehavioral Scales. Controlling for confounders, interactions between DNA methylation of these genes were detected for distinct domains of neurobehavior (habituation, excitability, asymmetrical reflexes). Moreover, different patterns of DNA methylation across the cortisol regulation pathway associated with different neurobehavioral phenotypes. Those with low NR3C1 methylation but high HSD11B2 methylation had lower excitability scores; those with high NR3C1 methylation but low HSD11B2 methylation had more asymmetrical reflexes; those with high DNA methylation across the entire pathway had higher habituation scores. These results suggest that epigenetic alterations across the cortisol regulation pathway may contribute to different neurobehavioral phenotypes, likely though varying degrees of glucocorticoid exposure during gestation. While the postnatal environment may continue to affect neurobehavioral risk, this study provides novel insights into the molecular basis for fetal origins of mental conditions. Copyright © 2014. Published by Elsevier Ltd.

Predicting infant neurodevelopmental outcomes using the placenta?

Article

May 2014
TRENDS MOL MED

Identifying those infants most at risk for poor neurodevelopmental outcomes is crucial to allow for targeted surveillance or preventative interventions to be instigated from birth. One intriguing possibility is to use the molecular characteristics of the placenta at birth as a ‘molecular barometer’ of the in utero experience to predict future infant neurodevelopmental outcomes. Here we highlight the recent advances in the field and discuss the possibilities for an integrated approach across the ‘-omics’ categories.

Sex-specific associations between placental leptin promoter DNA methylation and infant neurobehavior

Article

Feb 2014

Background Leptin (LEP) is a hormone central for energy homeostasis and has been implicated in neurodevelopment. This adipokine is produced by the placenta and is epigenetically regulated by promoter DNA methylation. Recent evidence has suggested a role for LEP in behavioral development. In this study, we investigated associations between profiles of human newborn neurobehavior and placental LEP DNA methylation. Methods We determined LEP promoter methylation in 444 placental samples from healthy term infants and measured LEP gene expression in a random subset of these samples. Infant neurobehavior was assessed with the NICU Network Neurobehavioral Scales (NNNS) and we examined the relationship between LEP promoter methylation and profiles of infant neurobehavior derived from these scores generated using a hierarchical model-based clustering method. Results LEP methylation is negatively correlated with gene expression only in placentas from male infants (r = −0.6, P = 0.006). A 10% increase in LEP DNA methylation was associated with membership in a profile of infant neurobehavior marked by increased lethargy and hypotonicity (OR = 1.9; 95% CI: 1.07–3.4), and consistently with reduced risk of membership in a profile characterized by decreased lethargy and hypotonicity (OR = 0.54; 95% CI: 0.3–0.94) only in male infants (n = 223). No statistically significant associations were observed amongst female infants. Discussion These results suggest that increased placental LEP DNA methylation, related to reduced expression, may play a role in human newborn neurodevelopment, particularly in reactivity to various stimuli, but that these effects may be sexually dimorphic.

MicroRNAs: Fundamental regulators of gene expression in major affective disorders and suicidal behavior?

Article

Nov 2013

A Flexible Analysis Tool for the Quantitative Acoustic Assessment of Infant Cry

Article

Jun 2013
J SPEECH LANG HEAR R

Purpose: In this article, the authors describe and validate the performance of a modern acoustic analyzer specifically designed for infant cry analysis. Method: Utilizing known algorithms, the authors developed a method to extract acoustic parameters describing infant cries from standard digital audio files. They used a frame rate of 25 ms with a frame advance of 12.5 ms. Cepstral-based acoustic analysis proceeded in 2 phases, computing frame-level data and then organizing and summarizing this information within cry utterances. Using signal detection methods, the authors evaluated the accuracy of the automated system to determine voicing and to detect fundamental frequency (F 0) as compared to voiced segments and pitch periods manually coded from spectrogram displays. Results: The system detected F 0 with 88% to 95% accuracy, depending on tolerances set at 10 to 20 Hz. Receiver operating characteristic analyses demonstrated very high accuracy at detecting voicing characteristics in the cry samples. Conclusions: This article describes an automated infant cry analyzer with high accuracy to detect important acoustic features of cry. A unique and important aspect of this work is the rigorous testing of the system's accuracy as compared to ground-truth manual coding. The resulting system has implications for basic and applied research on infant cry development.

Childhood maltreatment and methylation of the glucocorticoid receptor gene NR3C1 in bipolar disorder

Article

Jun 2013
BRIT J PSYCHIAT

Background Early-life adversities represent risk factors for the development of bipolar affective disorder and are associated with higher severity of the disorder. This may be the consequence of a sustained alteration of the hypothalamic-pituitary-adrenal (HPA) axis resulting from epigenetic modifications of the gene coding for the glucocorticoid receptor (NR3C1). Aims To investigate whether severity of childhood maltreatment isassociated with increased methylation of the exon 1F NR3C1 promoter in bipolar disorder. Method A sample of people with bipolar disorder (n = 99) were assessed for childhood traumatic experiences. The percentage of NR3C1 methylation was measured for each participant.Results The higher the number of trauma events, the higher was the percentage of NR3C1 methylation (β = 0.52, 95% CI 0.46-0.59, P"0.0001). The severity of each type of maltreatment (sexual, physical and emotional) was also associated with NR3C1 methylation status. Conclusions Early-life adversities have a sustained effect on the HPA axis through epigenetic processes and this effect may be measured in peripheral blood. This enduring biological impact of early trauma may alter the development of the brain and lead to adult psychopathological disorder. Declaration of interest None.

The ever growing complexity of placental epigenetics – Role in adverse pregnancy outcomes and fetal programming

Article

Oct 2012

As the primary interface between maternal and fetal circulations, the placenta is subject to a myriad of environmental exposures with the capacity to alter placental function and fetal development. Many of these effects are likely to be mediated by epigenetic ('above DNA') change, which is also in turn regulated by maternal and fetal genetic factors. Linking specific environmental exposures, genetic, and epigenetic variation to maternal and fetal outcomes may provide valuable mechanistic insights into the role of placental dysfunction in pregnancy-associated disease and later health. The complexities are manifold but are rapidly being overcome by technological advances and emerging analytical approaches. Although focussing on recent genome-scale and gene-specific DNA methylation studies in the human placenta, this review also discusses the potential of a future broader exploration of combined environmental, genetic and epigenomic approaches, encompassing higher order epigenetic modifications, for unravelling the molecular mechanisms underlying gene-environment interaction at the fetomaternal interface.

Placenta-Imprinted Gene Expression Association of Infant Neurobehavior

Article

Dec 2011

To identify links between altered gene imprinting in the placenta and infant neurobehavioral profiles. Quantitative reverse-transcription polymerase chain reaction was used to examine the expression of 22 imprinted candidate genes in a series of 106 term human primary placenta tissues. The expression pattern uncovered was associated with Neonatal Intensive Care Unit Network Neurobehavioral Scales summary scores in the corresponding infants. Clustering of the expression data was used to define distinct classes of expression. Significant associations were identified between classes of expression and the Neonatal Intensive Care Unit Network Neurobehavioral Scales quality of movement (P = .02) and handling (P = .006) scores. Multivariate regression demonstrated an independent effect of imprinted gene expression profile on these neurobehavioral scores after controlling for confounders. These results suggest that alterations in imprinted gene expression in the placenta are associated with infant neurodevelopmental outcomes, and suggest a role for the placenta and genomic imprinting in the placenta beyond intrauterine growth regulation.

Neonatal Neurobehavior Predicts Medical and Behavioral Outcome

Article

Dec 2009
Pediatrics

This study examined the NICU Network Neurobehavioral Scale (NNNS) as a predictor of negative medical and behavioral findings at 1 month to 4.5 years of age. The sample included 1248 mother-infant dyads (42% born at <37 weeks' gestational age [GA]) who were participating in a longitudinal study of the effects of prenatal substance exposure on child development. Mothers were recruited at 4 urban university-based centers and were mostly black and on public assistance. At 1 month of age, infants were tested with the NNNS. Latent profile analysis was conducted on NNNS summary scales to identify discrete behavioral profiles. The validity of the NNNS was examined by using logistic regression to predict prenatal drug exposure and medical and developmental outcomes through 4.5 years of age including adjustment for GA and socioeconomic status. Five discrete behavioral profiles were reliably identified; the most extreme negative profile was found in 5.8% of the infants. The profiles showed statistically significant associations with prenatal drug exposure; GA and birth weight; head ultrasound; neurologic and brain disease findings; and abnormal scores on measures of behavior problems, school readiness, and IQ through 4.5 years of age. The NNNS may be useful to identify infant behavioral needs to be targeted in well-infant pediatric care, as well as for referrals to community-based early intervention services.

Epigenetics in the placenta. Am J Reprod Immunol

Article

Sep 2009
AM J REPROD IMMUNOL

Epigenetics is focused on understanding the control of gene expression beyond what is encoded in the sequence of DNA. Central to growing interest in the field is the hope that more can be learned about the epigenetic regulatory mechanisms underlying processes of human development and disease. Researchers have begun to examine epigenetic alterations - such as changes in promoter DNA methylation, genomic imprinting, and expression of miRNA - to learn more about epigenetic regulation in the placenta, an organ whose proper development and function are crucial to the health, growth, and survival of the developing fetus. A number of studies are now making important links between alterations to appropriate epigenetic regulation in the placenta and diseases of gestation and early life. In addition, these studies are adding important insight into our understanding of trophoblast biology and differentiation as well as placental immunology. Examining epigenetic alterations in the placenta will prove especially important in the search for biomarkers of exposure, pathology, and disease risk and can provide critical insights into the biology of development and pathogenesis of disease. Thus, epigenetic alterations may aid in disease diagnosis and prognosis as well as in targeting new treatment and prevention strategies.

Neurobehavior at Term and White and Gray Matter Abnormalities in Very Preterm Infants

Article

Apr 2009

To examine the relationship between very preterm infant neurobehavior at term and concurrent magnetic resonance-defined cerebral abnormalities. 168 very preterm infants (birth weight <1250 g or gestation <30 weeks) were examined at term with 2 standardized neurobehavioral assessments, the Revised Hammersmith Neonatal Neurological Examination and the Neonatal Intensive Care Unit Network Neurobehavioral Scale. The relationship between composite neurobehavioral scores and qualitative white and gray matter abnormalities on magnetic resonance imaging was determined. Poorer neurobehavioral performance related to magnetic resonance-defined cerebral abnormalities. Composite neurobehavioral scores related to the total grade of white matter abnormality, and worse neurobehavior related most strongly to 2 components of this grade: white matter signal abnormalities and reduction in white matter volumes. Neurobehavior was not related to the total grade of gray matter abnormality. However, delayed gyral maturation, a component of the total gray matter grade, was related to poorer performance on both neurobehavioral scales. Very preterm infant neurobehavior at term is related to concurrent cerebral abnormalities in both white and gray matter defined by qualitative magnetic resonance imaging.

The Infant's Response to Entrapment Between Contradictory Messages in Face-to-Face Interaction

Article

Feb 1978
J Am Acad Child Psychiatr

The normal feedback infants receive from their mothers in face-to-face interaction was distorted by having the mothers face their infants but remain facially unresponsive. The infants studied reacted with intense wariness and eventual withdrawal, demonstrating the importance of interactional reciprocity and the ability of infants to regulate their emotional displays.

Developmental outcome prediction from acoustic analysis in term and preterm infants

Article

Nov 1987

Barry M. Lester

It has been suggested that the cry may reflect the neurophysiologic integrity of the infant and relate to later developmental outcome. In this study, the cry was recorded at term conceptional age in 18 preterm and 13 term infants using a standardized procedure and analyzed by high-speed computer. At 18 months of age, a significant number of infants were correctly classified as scoring high or low on the Bayley Scales of Infant Development based on the mean and variability in the fundamental frequency, variability in the first formant, and the amplitude of the cry. At 5 years of age, a significant number of infants were correctly classified on the McCarthy General Cognitive Index and on the verbal, perceptual-performance, and quantitative subscales based on the variability of the fundamental frequency, variability of the first formant, and amplitude and duration of the cry. Although preliminary, this study supports the potential use of the cry as a noninvasive measure to detect developmental outcome in the infant at risk.

Developmental Outcome as a Function of the Goodness of Fit Between the Infant's Cry Characteristics and the Mother's Perception of Her Infant's Cry

Article

Apr 1995

To determine whether the "goodness of fit" between infant cry characteristics and the mother's perception of the cry is related to developmental outcome at 18 months of age. This was a prospective, longitudinal study from birth to 18 months performed in a blinded manner. The study was conducted in a maternity hospital, including normal and special care nurseries and a laboratory for developmental follow-up. The 121 term and preterm infants and their mothers were selected to meet medical criteria. Acoustic analysis of 1-month infant cry and the mother's perception of the same cry was used to divide subjects into four groups representing matches and mismatches between infant cry characteristics and maternal cry perception. Primary outcome measures of cognitive, language, motor, and neurologic outcome were administered at 18 months. Caretaking environment measures were also recorded. Statistically significant (P < .05) findings showed that matched groups scored higher on measures of language and cognitive performance than infants in the mismatch groups, with a particular advantage for infants in the matched group in which mothers accurately perceived the higher-pitched cries of their infants. There were no differences between the groups in biologic or sociodemographic factors. Group differences were observed in social support and maternal self-esteem. Matches and mismatches between infant cry characteristics at 1 month and the mother's perception of the cry are related to cognitive and language outcome at 18 months in term and preterm infants. This relation is probably due to transactional processes in which developmental outcome is affected by the clarity of the infants' signals and by the ability of the mother to accurately perceive her infant's signals. The mother's ability to read her infant's cues may be affected by factors such as social support and self-esteem.

The placenta as the third brain

Article

May 1994
J REPROD MED

S. S. C. Yen

The placenta has enormous genetic endowments, comparable to those of the brain and ovary. The molecular, cellular and vascular arrangements are designed for directing the traffic of biochemical and nutritional flow preferentially to the fetus. The architect and landscape of this powerful organ, with a predetermined life span of 40 weeks, serves as a modulator between compartments via local, nearby and long-distance communications through its hormonal signals. Thus, the placenta may be viewed as the third brain, which links the developed (maternal) and developing (fetal) brains.

Living with the Past: Evolution, Development, and Patterns of Disease

Article

Oct 2004
SCIENCE

Epidemiological observations have led to the hypothesis that the risk of developing some chronic noncommunicable diseases in adulthood is influenced not only by genetic and adult life-style factors but also by environmental factors acting in early life. Research in evolutionary biology, developmental biology, and animal and human physiology provides support for this idea and suggests that environmental processes influencing the propensity to disease in adulthood operate during the periconceptual, fetal, and infant phases of life. This “developmental origins of health and disease” concept may have important biological, medical, and socioeconomic implications.

Assessment of infant cry: Acoustic cry analysis and parental perception

Article

Feb 2005

Infant crying signals distress to potential caretakers who can alleviate the aversive conditions that gave rise to the cry. The cry signal results from coordination among several brain regions that control respiration and vocal cord vibration from which the cry sounds are produced. Previous work has shown a relationship between acoustic characteristics of the cry and diagnoses related to neurological damage, SIDS, prematurity, medical conditions, and substance exposure during pregnancy. Thus, assessment of infant cry provides a window into the neurological and medical status of the infant. Assessment of infant cry is brief and noninvasive and requires recording equipment and a standardized stimulus to elicit a pain cry. The typical protocol involves 30 seconds of crying from a single application of the stimulus. The recorded cry is submitted to an automated computer analysis system that digitizes the cry and either presents a digital spectrogram of the cry or calculates measures of cry characteristics. The most common interpretation of cry measures is based on deviations from typical cry characteristics. Another approach evaluates the pattern across cry characteristics suggesting arousal or under-arousal or difficult temperament. Infants with abnormal cries should be referred for a full neurological evaluation. The second function of crying--to elicit caretaking--involves parent perception of the infant's needs. Typically, parents are sensitive to deviations in cry characteristics, but their perception can be altered by factors in themselves (e.g., depression) or in the context (e.g., culture). The potential for cry assessment is largely untapped. Infant crying and parental response is the first language of the new dyadic relationship. Deviations in the signal and/or misunderstanding the message can compromise infant care, parental effectiveness, and undermine the budding relationship. (c) 2005 Wiley-Liss, Inc. MRDD Research Reviews 2005;11:83-93.

Maternal care as a model for experience-dependent chromatin plasticity?

Article

Oct 2005
TRENDS NEUROSCI

It is widely acknowledged that the nature of the maternal care a child receives can have long-term repercussions, and that children raised in deprived environments can have severe cognitive and behavioural difficulties that last into adulthood. The mechanisms underlying these effects are not understood, but recent data from rodents provide insight into a potential molecular mechanism. Like humans, rodent maternal behaviour towards offspring can effect long-term changes in responses of the offspring to stress throughout the rest of their lives. Remarkably, these changes reflect permanently altered gene expression, so-called "environmental programming", and its downstream effects on the hypothalamic-pituitary-adrenal axis. This review discusses the nature of this environmental programming--the mechanism by which it occurs in rats, its long-term implications, and opportunities for its reversal in rodents and ultimately in humans.

Bird A. Perceptions of epigenetics. Nature 447: 396-398

Article

Jun 2007
NATURE

Adrian Bird

Geneticists study the gene; however, for epigeneticists, there is no obvious 'epigene'. Nevertheless, during the past year, more than 2,500 articles, numerous scientific meetings and a new journal were devoted to the subject of epigenetics. It encompasses some of the most exciting contemporary biology and is portrayed by the popular press as a revolutionary new science--an antidote to the idea that we are hard-wired by our genes. So what is epigenetics?

Glucocorticoids, developmental 'programming' and the risk of affective dysfunction. Prog

Article

Feb 2008
Progr Brain Res

Jonathan Seckl

Early life environmental events have persisting effects on tissue structure and function, a phenomenon called 'developmental programming'. Exposure to stress and its glucocorticoid hormone mediators may underpin many such effects. Indeed, studies in animal models and observations in humans suggest that prenatal stress/glucocorticoid overexposure causes permanent cardiometabolic, neuroendocrine and behavioural effects in offspring. Such effects appear mediated via tissue-specific changes in gene expression. Underlying epigenetic changes in target gene promoters may ensure persistence of altered transcription long after the initial challenge. Posttraumatic stress disorder and other affective diseases may both act as environmental challenges if present in early life and may themselves be more likely in individuals made 'vulnerable' by early life stress.

Epigenetic mechanisms in the placenta related to infant neurodevelopment

Abstract

No full-text available

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