Prenatal alcohol exposure is associated with changes in placental gene co-expression networks.

Alcohol consumption during pregnancy can result in a range of adverse postnatal outcomes among exposed children. However, identifying at-risk children is challenging given the difficulty to confirm prenatal alcohol exposure and the lack of early diagnostic tools. Placental surveys present an important opportunity to uncover early biomarkers to identify those at risk. Here, we report the first transcriptome-wide evaluation to comprehensively evaluate human placental pathways altered by fetal alcohol exposure. In a prospective longitudinal birth cohort in Cape Town, South Africa, we performed bulk tissue RNAseq in placenta samples from 32 women reporting heavy drinking during pregnancy and 30 abstainers/light drinkers. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis were performed to assess associations between fetal alcohol exposure and placental gene expression patterns at a network-wide and single gene level, respectively. The results revealed altered expression in genes related to erythropoiesis and angiogenesis, which are implicated in established postnatal phenotypes related to alcohol exposure, including disruptions in iron homeostasis, growth, and neurodevelopment. The reported findings provide insights into the molecular pathways affected by prenatal alcohol exposure and highlight the potential of placental biomarkers for detecting and understanding the effects of alcohol on fetal development.

RNA-seq analysis reveals prenatal alcohol exposure is associated with placental inflammatory cells and gene expression.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) are the most common preventable cause of birth defects and neurodevelopmental disorders worldwide. The placenta is the crucial interface between mother and fetus. Prenatal alcohol exposure (PAE) has been shown to alter placental structure and expression of genes in bulk placental tissue samples, but prior studies have not examined effects on placental cell-type composition or taken cell-type into consideration in transcriptome analyses. METHODS: We leveraged an existent placenta single-cell RNA-seq dataset to perform cell-type deconvolution of bulk placental RNA-seq data from 35 heavy drinking pregnant women and 33 controls in a prospective birth cohort in Cape Town, South Africa. We used bivariate analyses and multivariable adjusted linear regression models to assess the relation of PAE on inferred placental cell-type proportions. We also examined differential expression of inflammatory response genes and PAE, using multivariable adjusted linear models. RESULTS: Deconvolution analyses showed heterogeneous placenta cell-type composition in which stromal (27 %), endothelial (26 %) and cytotrophoblasts (18 %) were the predominant cell-types. PAE around conception was associated with a higher proportion of Hofbauer cells (B = 0.51, p = 0.035) in linear models adjusted for maternal age, infant sex, and gestational age. Among the 652 inflammatory genes examined, 35 were differential expressed in alcohol exposed placentas (FDR p < 0.05). CONCLUSIONS: Our findings suggest that heavy alcohol exposure during pregnancy can influence the proportion of fetal placental villi macrophages (Hofbauer cells) and increased expression of inflammatory genes. Future studies are needed to further characterize these effects and to assess the potential functional roles of placental inflammation in FASD.

Alterations in Placental Inflammation-Related Gene Expression Partially Mediate the Effects of Prenatal Alcohol Consumption on Maternal Iron Homeostasis.

Prenatal alcohol exposure (PAE) is associated with alterations in maternal and infant iron homeostasis that are consistent with changes seen in the setting of inflammation. We hypothesized that PAE leads to alterations in the placental expression of genes related to iron metabolism and inflammation that play functional roles in the teratogenic effects of alcohol on iron homeostasis. A total of 126 heavy-drinking women (≥1 oz (30 mL) absolute alcohol/day (~1.67 standard drinks/day) or women reporting binge drinking (≥2 drinks/occasion)) and 80 control women (<0.5 oz AA per day, no binging) in Cape Town, South Africa were interviewed prenatally regarding demographics, and alcohol, smoking, and drug use around conception and during pregnancy. Prenatal/maternal and infant hemoglobin and ferritin were measured. Whole-transcriptome RNA sequencing analysis was performed on flash-frozen transplacental tissue samples. Gene sets related to iron metabolism (n = 398) and inflammation (n = 467) were constructed by searching the Molecular Signatures Database for related ontology terms. Principal component analysis (PCA) yielded 59 factors for each theme. In multivariable regression models, PAE was related to 2 iron metabolism PCA factors (PCs) and 5 inflammation PCs, among which 2 iron metabolism and 4 inflammation factors were related to at least 1 key maternal or infant iron outcome. In causal inference analyses based on marginal structural models and the product method, the alterations in the expression profile of genes with functions in immune cell regulation, cytokine activity, angiogenesis, hematopoiesis, and ubiquitous cell processes appeared to partially mediate the relation of prenatal drinking frequency (days/week) around conception to a lower maternal hemoglobin-to-log(ferritin) ratio (proportion mediation = 51.35%). These findings suggest that placental inflammation may be partly responsible for the differences in alcohol-related iron homeostasis patterns between pregnant and non-pregnant adults.

Prioritization of potential causative genes for schizophrenia in placenta.

Our earlier work has shown that genomic risk for schizophrenia converges with early life complications in affecting risk for the disorder and sex-biased neurodevelopmental trajectories. Here, we identify specific genes and potential mechanisms that, in placenta, may mediate such outcomes. We performed TWAS in healthy term placentae (N = 147) to derive candidate placental causal genes that we confirmed with SMR; to search for placenta and schizophrenia-specific associations, we performed an analogous analysis in fetal brain (N = 166) and additional placenta TWAS for other disorders/traits. The analyses in the whole sample and stratifying by sex ultimately highlight 139 placenta and schizophrenia-specific risk genes, many being sex-biased; the candidate molecular mechanisms converge on the nutrient-sensing capabilities of placenta and trophoblast invasiveness. These genes also implicate the Coronavirus-pathogenesis pathway and showed increased expression in placentae from a small sample of SARS-CoV-2-positive pregnancies. Investigating placental risk genes for schizophrenia and candidate mechanisms may lead to opportunities for prevention that would not be suggested by study of the brain alone.

A Systematic Review of the Placental Translocation of Micro- and Nanoplastics.

PURPOSE OF REVIEW: Despite increasing awareness of the ubiquity of microplastics (MPs) in our environments, little is known about their risk of developmental toxicity. Even less is known about the environmental distribution and associated toxicity of nanoplastics (NPs). Here, we review the current literature on the capacity for MPs and NPs to be transported across the placental barrier and the potential to exert toxicity on the developing fetus. RECENT FINDINGS: This review includes 11 research articles covering in vitro, in vivo, and ex vivo models, and observational studies. The current literature confirms the placental translocation of MPs and NPs, depending on physicochemical properties such as size, charge, and chemical modification as well as protein corona formation. Specific transport mechanisms for translocation remain unclear. There is emerging evidence of placental and fetal toxicity due to plastic particles based on animal and in vitro studies. Nine out of eleven studies examined in this review found that plastic particles were capable of placental translocation. In the future, more studies are needed to confirm and quantify the existence of MPs and NPs in human placentas. Additionally, translocation of different plastic particle types and heterogenous mixtures across the placenta, exposure at different periods of gestation, and associations with adverse birth and other developmental outcomes should also be investigated.

Ethnic disparities in ambient air and traffic-related pollution exposure and ethnic-specific impacts on clinical biomarker levels.

BACKGROUND: Although characterizing the inequality in pollution exposure burden across ethnic groups and the ethnic-specific exposure associations is of great social and public health importance, it has not been systematically investigated in large population studies. METHODS: The UK Biobank data (N = 485, 806) of individual-level air ambient and traffic-related pollution exposure, biomarkers routinely used in clinical practice, genotype, life-style factors, and socioeconomic status were analyzed. Air pollution exposure estimates were compared among six genetically inferred ethnic groups. We also quantified the association between exposure and biomarkers within and across ethnicities. RESULTS: Non-European participants (defined by genetics) disproportionately bear a higher burden of exposure than their European counterparts even after adjusting for covariables including socioeconomic status. For example, exposure to NO2 in people with African ancestry was 30.7 % higher (p = 1.5E-786) than European subjects. Within the genetically defined African group, larger African genetic ancestry proportion (AGAP) was linked to higher ambient air pollutant exposure. Trans-Ethnic analysis identified 32 clinical biomarkers associated with environmental exposure. For 13 biomarkers, the association with exposure was significantly different or even in opposing directions across ethnic groups. CONCLUSIONS: Substantial disparities in air pollution exposure was observed among genetically-defined ethnic groups. Most importantly, we show that the impact of exposure on biomarkers varies by ethnicity. Reducing the disproportionally high exposure burden on non-European populations and alleviating the adverse consequences in an ethnic-specific manner are of great urgency and significance.

Variation in placental microRNA expression associates with maternal family history of cardiovascular disease.

In the United States, cardiovascular disease is the leading cause of death and the rate of maternal mortality remains among the highest of any industrialized nation. Maternal cardiometabolic health throughout gestation and postpartum is representative of placental health and physiology. Both proper placental functionality and placental microRNA expression are essential to successful pregnancy outcomes, and both are highly sensitive to genetic and environmental sources of variation. Placental pathologies, such as preeclampsia, are associated with maternal cardiovascular health but may also contribute to the developmental programming of chronic disease in offspring. However, the role of more subtle alterations to placental function and microRNA expression in this developmental programming remains poorly understood. We performed small RNA sequencing to investigate microRNA in placentae from the Rhode Island Child Health Study (n = 230). MicroRNA counts were modeled on maternal family history of cardiovascular disease using negative binomial generalized linear models. MicroRNAs were considered to be differentially expressed at a false discovery rate (FDR) less than 0.10. Parallel mRNA sequencing data and bioinformatic target prediction software were then used to identify potential mRNA targets of differentially expressed microRNAs. Nine differentially expressed microRNAs were identified (FDR < 0.1). Bioinformatic target prediction revealed 66 potential mRNA targets of these microRNAs, many of which are implicated in TGFß signaling pathway but also in pathways involving cellular metabolism and immunomodulation. A robust association exists between familial cardiovascular disease and placental microRNA expression which may be implicated in both placental insufficiencies and the developmental programming of chronic disease.

Placental Gene Transcript Proportions are Altered in the Presence of In Utero Arsenic and Cadmium Exposures, Genetic Variants, and Birth Weight Differences.

Background: In utero arsenic and cadmium exposures are linked with reduced birth weight as well as alterations in placental molecular features. However, studies thus far have focused on summarizing transcriptional activity at the gene level and do not capture transcript specification, an important resource during fetal development to enable adaptive responses to the rapidly changing in utero physiological conditions. In this study, we conducted a genome-wide analysis of the placental transcriptome to evaluate the role of differential transcript usage (DTU) as a potential marker of in utero arsenic and cadmium exposure and fetal growth restriction. Methods: Transcriptome-wide RNA sequencing was performed in placenta samples from the Rhode Island Child Health Study (RICHS, n = 199). Arsenic and cadmium levels were measured in maternal toenails using ICP-MS. Differential transcript usage (DTU) contrasting small (SGA) and appropriate (AGA) for gestational age infants as well as above vs. below median exposure to arsenic and cadmium were assessed using the DRIMSeq R package. Genetic variants that influence transcript usage were determined using the sQTLseeker R package. Results: We identified 82 genes demonstrating DTU in association with SGA status at an FDR <0.05. Among these, one gene, ORMDL1, also demonstrated DTU in association with arsenic exposure, and fifteen genes (CSNK1E, GBA, LAMTOR4, MORF4L1, PIGO, PSG1, PSG3, PTMA, RBMS1, SLC38A2, SMAD4, SPCS2, TUBA1B, UBE2A, YIPF5) demonstrated DTU in association with cadmium exposure. In addition to cadmium exposure and SGA status, proportions of the LAMTOR4 transcript ENST00000474141.5 also differed by genetic variants (rs10231604, rs12878, and rs3736591), suggesting a pathway by which an in utero exposure and genetic variants converge to impact fetal growth through perturbations of placental processes. Discussion: We report the first genome-wide characterization of placental transcript usage and associations with intrauterine metal exposure and fetal growth restriction. These results highlight the utility of interrogating the transcriptome at finer-scale transcript-level resolution to identify novel placental biomarkers of exposure-induced outcomes.

PM2.5 exposure during pregnancy is associated with altered placental expression of lipid metabolic genes in a US birth cohort.

Inhalation of ambient PM2.5, shown to be able to cross the placenta, has been linked to adverse obstetric and postnatal metabolic health outcomes. The placenta regulates fetal growth and influences postnatal development via fetal programming. Placental gene expression may be influenced by intrauterine exposures to PM2.5. Herein, we explore whether maternal PM2.5 exposure during pregnancy alters placental gene expression related to lipid and glucose metabolism in a U.S. birth cohort, the Rhode Island Child Health Study (RICHS). Average PM2.5 exposure level was estimated linking residential addresses and satellite data across the three trimesters using spatio-temporal models. Based on Gene Ontology annotations, we curated a list of 657 lipid and glucose metabolism genes. We conducted a two-staged analysis by leveraging placental RNA-Seq data from 148 subjects to identify top dysregulated metabolic genes associated with PM2.5 (Phase I) and then validated the results in placental samples from 415 participants of the cohort using RT-qPCR (Phase II). Associations between PM2.5 and placental gene expression were explored using multivariable linear regression models in the overall population and in sex-stratified analyses. The average level of PM2.5 exposure across pregnancy was 8.0µg/m3, which is below the national standard of 12µg/m3. Phase I revealed that expression levels of 32 out of the curated list of 657 genes were significantly associated with PM2.5 exposure (FDR P<0.01), 28 genes showed differential expression modified by sex of the infant. Five of these genes (ABHD3, ATP11A, CLTCL1, ST6GALNAC4 and PSCA) were validated using RT-qPCR. Associations were stronger in placentas from male births compared to females, indicating a sex-dependent effect. These genes are involved in inflammation, lipid transport, cell-cell communication or cell invasion. Our results suggest that gestational PM2.5 exposure may alter placental metabolic function. However, whether it confers long-term programming effects postnatally, especially in a sex-specific matter, warrants further studies.

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

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 prenatal alcohol-related alterations in imprinted gene methylation and/or expression and discuss potential mechanistic roles for these alterations 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.

Placental gene network modules are associated with maternal stress during pregnancy and infant temperament.

Maternal psychosocial stress during pregnancy (MPSP) is a known contributor to maladaptive neurobehavioral development of the offspring; however, the underlying molecular mechanisms linking MPSP with childhood outcome remain largely unknown. Transcriptome-wide gene expression data were generated using RNA-seq from placenta samples collected in a multi-ethnic urban birth cohort in New York City (n = 129). Weighted gene co-expression network analysis (WGCNA) was used to characterize placental co-expression modules, which were then evaluated for their associations with MPSP and infant temperament. WGCNA revealed 16 gene coexpression modules. One module, enriched for regulation of chromosome organization/gene expression, was positively associated with MPSP and negatively associated with Regulatory Capacity (REG), a component of infant temperament. Two other modules, enriched for cotranslational protein targeting and cell cycle regulation, respectively, displayed negative associations with MPSP and positive associations with REG. A module enriched with oxidative phosphorylation/mitochondrial translation was positively associated with REG. These findings support the notion that the placenta provides a functional in utero link between MPSP and infant temperament, possibly through transcriptional regulation of placental gene expression.

Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth.

Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.

Placental gene networks at the interface between maternal PM2.5 exposure early in gestation and reduced infant birthweight.

BACKGROUND: A growing body of evidence links maternal exposure to particulate matter <2.5 µM in diameter (PM2.5) and deviations in fetal growth. Several studies suggest that the placenta plays a critical role in conveying the effects of maternal PM2.5 exposure to the developing fetus. These include observed associations between air pollutants and candidate placental features, such as mitochondrial DNA content, DNA methylation and telomere length. However, gaps remain in delineating the pathways linking the placenta to air pollution-related health effects, including a comprehensive profiling of placental processes impacted by maternal PM2.5 exposure. In this study, we examined alterations in a placental transcriptome-wide network in relation to maternal PM2.5 exposure prior to and during pregnancy and infant birthweight. METHODS: We evaluated PM2.5 exposure and placental RNA-sequencing data among study participants enrolled in the Rhode Island Child Health Study (RICHS). Daily residential PM2.5 levels were estimated using a hybrid model incorporating land-use regression and satellite remote sensing data. Distributed lag models were implemented to assess the impact on infant birthweight due to PM2.5 weekly averages ranging from 12 weeks prior to gestation until birth. Correlations were assessed between PM2.5 levels averaged across the identified window of susceptibility and a placental transcriptome-wide gene coexpression network previously generated using the WGCNA R package. RESULTS: We identified a sensitive window spanning 12 weeks prior to and 13 weeks into gestation during which maternal PM2.5 exposure is significantly associated with reduced infant birthweight. Two placental coexpression modules enriched for genes involved in amino acid transport and cellular respiration were correlated with infant birthweight as well as maternal PM2.5 exposure levels averaged across the identified growth restriction window. CONCLUSION: Our findings suggest that maternal PM2.5 exposure may alter placental programming of fetal growth, with potential implications for downstream health effects, including susceptibility to cardiometabolic health outcomes and viral infections.

Placental microRNA expression associates with birthweight through control of adipokines: results from two independent cohorts.

MicroRNAs are non-coding RNAs that regulate gene expression post-transcriptionally. In the placenta, the master regulator of foetal growth and development, microRNAs shape the basic processes of trophoblast biology and specific microRNA have been associated with foetal growth. To comprehensively assess the role of microRNAs in placental function and foetal development, we have performed small RNA sequencing to profile placental microRNAs from two independent mother-infant cohorts: the Rhode Island Child Health Study (n = 225) and the New Hampshire Birth Cohort Study (n = 317). We modelled microRNA counts on infant birthweight percentile (BWP) in each cohort, while accounting for race, sex, parity, and technical factors, using negative binomial generalized linear models. We identified microRNAs that were differentially expressed (DEmiRs) with BWP at false discovery rate (FDR) less than 0.05 in both cohorts. hsa-miR-532-5p (miR-532) was positively associated with BWP in both cohorts. By integrating parallel whole transcriptome and small RNA sequencing in the RICHS cohort, we identified putative targets of miR-532. These targets are enriched for pathways involved in adipogenesis, adipocytokine signalling, energy metabolism, and hypoxia response, and included Leptin, which we further demonstrated to have a decreasing expression with increasing BWP, particularly in male infants. Overall, we have shown a robust and reproducible association of miR-532 with BWP, which could influence BWP through regulation of adipocytokines Leptin and Adiponectin.

Differences in Placental Imprinted Gene Expression across Preeclamptic and Non-Preeclamptic Pregnancies.

Preeclampsia is a multi-systemic syndrome that presents in approximately 5% of pregnancies worldwide and is associated with a range of subsequent postpartum and postnatal outcomes, including fetal growth restriction. As the placenta plays a critical role in the development of preeclampsia, surveying genomic features of the placenta, including expression of imprinted genes, may reveal molecular markers that can further refine subtypes to aid targeted disease management. In this study, we conducted a comprehensive survey of placental imprinted gene expression across early and late onset preeclampsia cases and preterm and term normotensive controls. Placentas were collected at delivery from women recruited at the Magee-Womens Hospital prenatal clinics, and expression levels were profiled across 109 imprinted genes. We observed downregulation of placental Mesoderm-specific transcript (MEST) and Necdin (NDN) gene expression levels (false discovery rate (FDR) < 0.05) among early onset preeclampsia cases compared to preterm controls. No differences in placental imprinted gene expression were observed between late onset preeclampsia cases and term controls. While few studies have linked NDN to pregnancy complications, reductions in MEST expression levels, as observed in our study, are consistently reported in the literature in relation to various pregnancy complications, including fetal growth restriction, suggesting a potential role for placental MEST expression as a biosensor of an adverse in utero environment.

Seasonally variant gene expression in full-term human placenta.

Seasonal exposures influence human health and development. The placenta, as a mediator of the maternal and fetal systems and a regulator of development, is an ideal tissue to understand the biological pathways underlying relationships between season of birth and later life health outcomes. Here, we conducted a differential expression (DE) analysis of season of birth in full-term human placental tissue to evaluate whether the placenta may be influenced by seasonal cues. Of the analyzed transcripts, 583 displayed DE between summer and winter births (False Discovery Rate [FDR] q < .05); among these, BHLHE40, MIR210HG, and HILPDA had increased expression among winter births (Bonferroni P < .05). Enrichment analyses of the seasonally variant genes between summer and winter births indicated overrepresentation of transcription factors HIF1A, VDR, and CLOCK, among others, and of GO term pathways related to ribosomal activity and infection. Additionally, a cosinor analysis found rhythmic expression for approximately 11.9% of all 17 664 analyzed placental transcripts. These results suggest that the placenta responds to seasonal cues and add to the growing body of evidence that the placenta acts as a peripheral clock, which may provide a molecular explanation for the extensive associations between season of birth and health outcomes.

Placental lncRNA expression associated with placental cadmium concentrations and birth weight.

Heavy metal exposures, such as cadmium, can have negative effects on infant birth weight (BW)-among other developmental outcomes-with placental dysfunction potentially playing a role in these effects. In this study, we examined how differential placental expression of long non-coding RNAs (lncRNAs) may be associated with cadmium levels in placenta and whether differences in the expression of those lncRNAs were associated with fetal growth. In the Rhode Island Child Health Study, we used data from Illumina HiSeq whole transcriptome RNA sequencing (n = 199) to examine association between lncRNA expression and measures of infant BW as well as placental cadmium concentrations controlled for appropriate covariates. Of the 1191 lncRNAs sequenced, 46 demonstrated associations (q < 0.05) with BW in models controlling for infant sex, maternal age, BMI, maternal education, and smoking during pregnancy. Furthermore, four of these transcripts were associated with placental cadmium concentrations, with MIR22HG and ERVH48-1 demonstrating increases in expression associated with increasing cadmium exposure and elevated odds of small for gestational age birth, while AC114763.2 and LINC02595 demonstrated reduced expression associated with cadmium, but elevated odds of large for gestational age birth with increasing expression. We identified relationships between lncRNA expression with both placental cadmium concentrations and BW. This study provides evidence that disrupted placental expression of lncRNAs may be a part of cadmium's mechanisms of reproductive toxicity.

Maternal stress in relation to sex-specific expression of placental genes involved in nutrient transport, oxygen tension, immune response, and the glucocorticoid barrier.

INTRODUCTION: Murine models provide evidence that maternal stress during pregnancy can influence placenta morphology and function, including altered expression of genes involved in the maintenance and progression of pregnancy and fetal development. Corresponding research evaluating the impact of maternal stress on placental gene expression in humans is limited. We examined maternal stress in relation to placental expression of 17 candidate genes in a community-based sample. METHODS: Participants included 60 mother-newborn pairs enrolled in the PRogramming of Intergenerational Stress Mechanisms pregnancy cohort based at the Mount Sinai Hospital in New York City. Placentas were collected immediately following delivery and gene expression was measured using a qPCR-based platform. Maternal experiences of traumatic and non-traumatic stress were measured using the Life Stressor Checklist-Revised (LSC-R) administered during a mid-pregnancy interview. We used multivariable linear regression to examine associations between LSC-R scores and expression of each gene in separate models in the sample overall and stratified by fetal sex. RESULTS: Higher maternal stress was associated with significantly increased placental expression of the nutrient sensor gene OGT, the glucose transporter gene GLUT1, and the hypoxia sensor gene HIF3A. In models stratified by fetal sex, significant associations remained only among males. DISCUSSION: This study represents one of the most comprehensive examinations of maternal lifetime traumatic and non-traumatic stress in relation to placental gene expression in human tissue. Our findings support that maternal stress may alter sex-specific placental expression of genes involved in critical developmental processes.

Moderate prenatal stress may buffer the impact of Superstorm Sandy on placental genes: Stress in Pregnancy (SIP) Study.

The placenta plays a central role in the epigenetic programming of neurodevelopment by prenatal stress (PS), but this pathway is not fully understood. It difficult to study in humans because the conditions for intense, traumatic PS are almost impossible to create ethically. This study was able to capitalize on a 2012 disaster that hit New York, Superstorm Sandy, to examine the impact of traumatic stress on placental gene expression while also examining normative PS, and compare the two. Of the 303 expectant mothers participating in the Stress in Pregnancy Study, 95 women were pregnant when Superstorm Sandy struck. During their pregnancy, participants completed self-report measures of PS and distress that were combined, using latent profile analysis, into one global indicator of normative PS. Placental tissue was collected at delivery and frozen for storage. RNA expression was assessed for 40 placental genes known to associate with the stress response system and neurodevelopment in offspring. Results showed that normative PS increased expression of just MECP2, HSD11B2, and ZNF507, whereas Superstorm Sandy PS decreased expression of CDKL5, CFL1, DYRK1A, HSD11B2, MAOA, MAOB, NCOR1, and ZNF507. Interaction analyses indicated that Superstorm Sandy PS was associated with decreased gene expression for the low and high PS group for CFL1, DYRK1A, HSD11B2, MAOA, and NCOR1 and increased expression for the moderate PS group for FOXP1, NR3C1, and NR3C2. This study supports the idea that a moderate amount of normative PS may buffer the impact of traumatic PS, in this case caused by Superstorm Sandy, on placental gene expression, which suggests that the placenta itself mirrors the organism's ability to develop an epigenetic resilience to, and inoculation from, stress.

In-depth characterization of the placental imprintome reveals novel differentially methylated regions across birth weight categories.

Imprinted genes play a pivotal role in placental processes underlying fetal development, and much interest centers on discerning whether these loci, via changes in DNA methylation and/or gene expression, inform disruptions in appropriate fetal growth. In this study, we comprehensively profiled DNA methylation across the placental imprintome and assessed the relationship with gene expression levels and aberrant fetal growth.Placental DNA methylation across 153 imprinted loci, including imprint control regions (ICR) and surrounding non-ICR regions, was surveyed using the Nimblegen TruSeq bisulfite sequencing platform among participants enrolled in the Rhode Island Child Health Study (RICHS, n = 163). Methylation and gene expression associations were assessed using eQTM analysis. Differential methylation analysis contrasting small (SGA) and large for gestational age (LGA) infants against appropriate for gestational age (AGA) infants was assessed using the DMRcate R package.We identified 34 SGA-related differentially methylated regions (DMRs) and 9 LGA-related DMRs (FDR<0.05), and these BW-DMRs predominated in promoter and intronic regions. We observed overall hypomethylation among SGA-DMRs overlapping maternally expressed (paternally imprinted) genes while no parent-of-origin effect was observed among LGA DMRs. Three BW-DMRs, mapping to GABRG3, IGF1R and MEST, were common to SGA and LGA placenta. We did not observe significant correlations between BW-DMR-associated CpG methylation and gene expression levels.We report the first in-depth characterization of the placental imprintome in a population-wide setting. Our findings reveal growth-related differences in methylation without concomitant expression differences in regions that extend beyond typically interrogated imprinted loci, highlighting potentially novel placental biomarkers of growth and development.