Publications by authors named "Lisa Smeester"

53 Publications

Differential placental CpG methylation is associated with chronic lung disease of prematurity.

Pediatr Res 2021 Dec 2. Epub 2021 Dec 2.

Department of Environmental Sciences and Engineering, Gilling School of Global Public Health, The University of North Carolina, Chapel Hill, NC, USA.

Background: Chronic lung disease (CLD) is the most common pulmonary morbidity in extremely preterm infants. It is unclear to what extent prenatal exposures influence the risk of CLD. Epigenetic variation in placenta DNA methylation may be associated with differential risk of CLD, and these associations may be dependent upon sex.

Methods: Data were obtained from a multi-center cohort of infants born extremely preterm (<28 weeks' gestation) and an epigenome-wide approach was used to identify associations between placental DNA methylation and CLD (n = 423). Associations were evaluated using robust linear regression adjusting for covariates, with a false discovery rate of 0.05. Analyses stratified by sex were used to assess differences in methylation-CLD associations.

Results: CLD was associated with differential methylation at 49 CpG sites representing 46 genes in the placenta. CLD was associated with differential methylation of probes within genes related to pathways involved in fetal lung development, such as p53 signaling and myo-inositol biosynthesis. Associations between CpG methylation and CLD differed by sex.

Conclusions: Differential placental methylation within genes with key roles in fetal lung development may reflect complex cell signaling between the placenta and fetus which mediate CLD risk. These pathways appear to be distinct based on fetal sex.

Impact: In extremely preterm infants, differential methylation of CpG sites within placental genes involved in pathways related to cell signaling, oxidative stress, and trophoblast invasion is associated with chronic lung disease of prematurity. DNA methylation patterns associated with chronic lung disease were distinctly based on fetal sex, suggesting a potential mechanism underlying dimorphic phenotypes. Mechanisms related to fetal hypoxia and placental myo-inositol signaling may play a role in fetal lung programming and the developmental origins of chronic lung disease. Continued research of the relationship between the placental epigenome and chronic lung disease could inform efforts to ameliorate or prevent this condition.
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http://dx.doi.org/10.1038/s41390-021-01868-xDOI Listing
December 2021

Pre-pregnancy BMI-associated miRNA and mRNA expression signatures in the placenta highlight a sexually-dimorphic response to maternal underweight status.

Sci Rep 2021 08 3;11(1):15743. Epub 2021 Aug 3.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and neonatal health outcomes, with differences in risk observed between sexes. Given that the placenta is a sexually dimorphic organ and critical regulator of development, examining differences in placental mRNA and miRNA expression in relation to pre-pregnancy BMI may provide insight into responses to maternal BMI in utero. Here, genome-wide mRNA and miRNA expression levels were assessed in the placentas of infants born extremely preterm. Differences in expression were evaluated according to pre-pregnancy BMI status (1) overall and (2) in male and female placentas separately. Overall, 719 mRNAs were differentially expressed in relation to underweight status. Unexpectedly, no genes were differentially expressed in relation to overweight or obese status. In male placentas, 572 mRNAs were associated with underweight status, with 503 (70%) overlapping genes identified overall. Notably, 43/572 (8%) of the mRNAs associated with underweight status in male placentas were also gene targets of two miRNAs (miR-4057 and miR-128-1-5p) associated with underweight status in male placentas. Pathways regulating placental nutrient metabolism and angiogenesis were among those enriched in mRNAs associated with underweight status in males. This study is among the first to highlight a sexually dimorphic response to low pre-pregnancy BMI in the placenta.
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http://dx.doi.org/10.1038/s41598-021-95051-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333418PMC
August 2021

Comparing the Predictivity of Human Placental Gene, microRNA, and CpG Methylation Signatures in Relation to Perinatal Outcomes.

Toxicol Sci 2021 09;183(2):269-284

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

Molecular signatures are being increasingly integrated into predictive biology applications. However, there are limited studies comparing the overall predictivity of transcriptomic versus epigenomic signatures in relation to perinatal outcomes. This study set out to evaluate mRNA and microRNA (miRNA) expression and cytosine-guanine dinucleotide (CpG) methylation signatures in human placental tissues and relate these to perinatal outcomes known to influence maternal/fetal health; namely, birth weight, placenta weight, placental damage, and placental inflammation. The following hypotheses were tested: (1) different molecular signatures will demonstrate varying levels of predictivity towards perinatal outcomes, and (2) these signatures will show disruptions from an example exposure (ie, cadmium) known to elicit perinatal toxicity. Multi-omic placental profiles from 390 infants in the Extremely Low Gestational Age Newborns cohort were used to develop molecular signatures that predict each perinatal outcome. Epigenomic signatures (ie, miRNA and CpG methylation) consistently demonstrated the highest levels of predictivity, with model performance metrics including R2 (predicted vs observed) values of 0.36-0.57 for continuous outcomes and balanced accuracy values of 0.49-0.77 for categorical outcomes. Top-ranking predictors included miRNAs involved in injury and inflammation. To demonstrate the utility of these predictive signatures in screening of potentially harmful exogenous insults, top-ranking miRNA predictors were analyzed in a separate pregnancy cohort and related to cadmium. Key predictive miRNAs demonstrated altered expression in association with cadmium exposure, including miR-210, known to impact placental cell growth, blood vessel development, and fetal weight. These findings inform future predictive biology applications, where additional benefit will be gained by including epigenetic markers.
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http://dx.doi.org/10.1093/toxsci/kfab089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478332PMC
September 2021

Development of the genomic inflammatory index (GII) to assess key maternal antecedents associated with placental inflammation.

Placenta 2021 08 18;111:82-90. Epub 2021 Jun 18.

Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

Introduction: Placental inflammation is associated with a variety of adverse health outcomes, including poor pregnancy outcomes as well as later in life health. The current clinical methodologies for evaluating placental histology for inflammation are limited in their sensitivity. The objective of this study was to develop a genomic inflammatory index (GII) that can be utilized as a biomarker to effectively quantify and evaluate placental inflammation.

Methods: RNA-sequencing of n = 386 placentas from the Extremely Low Gestational Age Newborn (ELGAN) cohort was conducted. Transcriptional data for a biologically-targeted set of 14 genes, selected for their established role in pro-inflammatory signaling pathways, were aggregated to construct the GII. Multiple linear regression models were used to examine relationships between 47 perinatal factors and the GII.

Results: The GII demonstrated a nine-fold difference across subjects and displayed positive trends with other indicators of placental inflammation. Significant differences in the GII were observed for race where women who self-identified as Black displayed higher levels of placental inflammation than those who self-identified as White women (p < 0.001). Additionally, married Black women showed reduced placental inflammation compared to those who were unmarried (beta value: 0.828, p-value: 0.032). Placentas from women who were treated with steroids during the delivery of the infant displayed higher GII levels than those who were not (p = 0.023).

Discussion: Overall, the GII demonstrated an association between various perinatal factors and placental inflammation. It is anticipated that the GII will provide a novel genomics tool for quantifying placental inflammation, allowing for further investigation of causes, and ultimately the prevention, of inflammation in the placenta.
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http://dx.doi.org/10.1016/j.placenta.2021.06.010DOI Listing
August 2021

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

Mol Autism 2020 12 11;11(1):97. Epub 2020 Dec 11.

Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.

Background: Children born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes.

Methods: We examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS.

Results: Genes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case-control status.

Limitations: The ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited.

Conclusions: Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.
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http://dx.doi.org/10.1186/s13229-020-00402-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730750PMC
December 2020

Identifying the Transcriptional Response of Cancer and Inflammation-Related Genes in Lung Cells in Relation to Ambient Air Chemical Mixtures in Houston, Texas.

Environ Sci Technol 2020 11 16;54(21):13807-13816. Epub 2020 Oct 16.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Atmospheric pollution represents a complex mixture of air chemicals that continually interact and transform, making it difficult to accurately evaluate associated toxicity responses representative of real-world exposure. This study leveraged data from a previously published article and reevaluated lung cell transcriptional response induced by outdoor atmospheric pollution mixtures using field-based exposure conditions in the industrialized Houston Ship Channel. The tested hypothesis was that individual and co-occurring chemicals in the atmosphere relate to altered expression of critical genes involved in inflammation and cancer-related processes in lung cells. Human lung cells were exposed at an air-liquid interface to ambient air mixtures for 4 h, with experiments replicated across 5 days. Real-time monitoring of primary and secondary gas-phase pollutants, as well as other atmospheric conditions, was simultaneously conducted. Transcriptional analysis of exposed cells identified critical genes showing differential expression associated with both individual and chemical mixtures. The individual pollutant identified with the largest amount of associated transcriptional response was benzene. Tumor necrosis factor () and interferon regulatory factor 1 () were identified as key upstream transcription factor regulators of the cellular response to benzene. This study is among the first to measure lung cell transcriptional responses in relation to real-world, gas-phase air mixtures.
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http://dx.doi.org/10.1021/acs.est.0c02250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757424PMC
November 2020

A role for microRNAs in the epigenetic control of sexually dimorphic gene expression in the human placenta.

Epigenomics 2020 09 9;12(17):1543-1558. Epub 2020 Sep 9.

Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

The contribution of miRNAs as epigenetic regulators of sexually dimorphic gene expression in the placenta is unknown. 382 placentas from the extremely low gestational age newborns (ELGAN) cohort were evaluated for expression levels of 37,268 mRNAs and 2,102 miRNAs using genome-wide RNA-sequencing. Differential expression analysis was used to identify differences in the expression based on the sex of the fetus. Sexually dimorphic expression was observed for 128 mRNAs and 59 miRNAs. A set of 25 miRNA master regulators was identified that likely contribute to the sexual dimorphic mRNA expression. These data highlight sex-dependent miRNA and mRNA patterning in the placenta and provide insight into a potential mechanism for observed sex differences in outcomes.
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http://dx.doi.org/10.2217/epi-2020-0062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607407PMC
September 2020

Placental genomic and epigenomic signatures associated with infant birth weight highlight mechanisms involved in collagen and growth factor signaling.

Reprod Toxicol 2020 09 25;96:221-230. Epub 2020 Jul 25.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; The Institute for Environmental Health Solutions, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Curriculum in Toxicology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

Birth weight (BW) represents an important clinical and toxicological measure, indicative of the overall health of the newborn as well as potential risk for later-in-life outcomes. BW can be influenced by endogenous and exogenous factors and is known to be heavily impacted in utero by the health and function of the placenta. An aspect that remains understudied is the influence of genomic and epigenomic programming within the placenta on infant BW. To address this gap, we set out to test the hypothesis that genes involved in critical placental cell signaling are associated with infant BW, and are likely regulated, in part, through epigenetic mechanisms based on microRNA (miRNA) mediation. This study leveraged a robust dataset based on 390 infants born at low gestational age (ranged 23-27 weeks) to evaluate genome-wide expression profiles of both mRNAs and miRNAs in placenta tissues and relate these to infant BW. A total of 254 mRNAs and 268 miRNAs were identified as associated with BW, the majority of which showed consistent associations across placentas derived from both males and females. BW-associated mRNAs were found to be enriched for important biological pathways, including glycoprotein VI (the major receptor for collagen), human growth, and hepatocyte growth factor signaling, a portion of which were predicted to be regulated by BW-associated miRNAs. These miRNA-regulated pathways highlight key mechanisms potentially linking endogenous/exogenous factors to changes in birth outcomes that may be deleterious to infant and later-in-life health.
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http://dx.doi.org/10.1016/j.reprotox.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855285PMC
September 2020

Isoprene-Derived Secondary Organic Aerosol Induces the Expression of MicroRNAs Associated with Inflammatory/Oxidative Stress Response in Lung Cells.

Chem Res Toxicol 2020 02 13;33(2):381-387. Epub 2019 Dec 13.

Department of Environmental Sciences & Engineering, Gillings School of Global Public Health , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.

Exposure to fine particulate matter (PM), of which secondary organic aerosol (SOA) is a major constituent, is linked to adverse health outcomes, including cardiovascular disease, lung cancer, and preterm birth. Atmospheric oxidation of isoprene, the most abundant nonmethane hydrocarbon emitted into Earth's atmosphere primarily from vegetation, contributes to SOA formation. Isoprene-derived SOA has previously been found to alter inflammatory/oxidative stress genes. MicroRNAs (miRNAs) are epigenetic regulators that serve as post-transcriptional modifiers and key mediators of gene expression. To assess whether isoprene-derived SOA alters miRNA expression, BEAS-2B lung cells were exposed to laboratory-generated isoprene-derived SOA constituents derived from the acid-driven multiphase chemistry of authentic methacrylic acid epoxide (MAE) or isomeric isoprene epoxydiols (IEPOX) with acidic sulfate aerosol particles. These IEPOX- and MAE-derived SOA constituents have been shown to be measured in large quantities within PM collected from isoprene-rich areas affected by acidic sulfate aerosol particles derived from human activities. A total of 29 miRNAs were identified as differentially expressed when exposed to IEPOX-derived SOA and 2 when exposed to MAE-derived SOA, a number of which are inflammatory/oxidative stress associated. These results suggest that miRNAs may modulate the inflammatory/oxidative stress response to SOA exposure, thereby advancing the understanding of airway cell epigenetic response to SOA.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243464PMC
February 2020

Acetaminophen use during pregnancy and DNA methylation in the placenta of the extremely low gestational age newborn (ELGAN) cohort.

Environ Epigenet 2019 Apr 6;5(2):dvz010. Epub 2019 Aug 6.

Curriculum in Toxicology and Environmental Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.

Acetaminophen is considered the safest antipyretic and analgesic medication for pregnant women. However, studies have reported that acetaminophen has endocrine disrupting properties and prenatal exposure has been associated with early life epigenetic changes and later life health outcomes. As the placenta is the central mediator of maternal and fetal interactions, exposure to acetaminophen during pregnancy could manifest as perturbations in the placenta epigenome. Here, we evaluated epigenome-wide cytosine-guanine dinucleotide (CpG) methylation in placental tissue in relation to maternal acetaminophen use during pregnancy in a cohort of 286 newborns born prior to 28 weeks gestation. According to maternal self-report, more than half (166 of 286) of the newborns were exposed to acetaminophen . After adjustment for potential confounders, a total of 42 CpGs were identified to be differentially methylated at a false discovery rate < 0.05, with most displaying increased methylation as it relates to acetaminophen exposure. A notable gene that was significantly associated with acetaminophen is the prostaglandin receptor () which plays an essential role in mediating placental blood flow and fetal growth. Moreover, for 6 of the 42 CpGs, associations of acetaminophen use with methylation were significantly different between male and female placentas; 3 CpG sites were associated with acetaminophen use in the male placenta and 3 different sites were associated with acetaminophen use in the female placenta (  < 0.2). These findings highlight a relationship between maternal acetaminophen use during pregnancy and the placental epigenome and suggest that the responses for some CpG sites are sex dependent.
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http://dx.doi.org/10.1093/eep/dvz010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682751PMC
April 2019

Placental CpG Methylation of Inflammation, Angiogenic, and Neurotrophic Genes and Retinopathy of Prematurity.

Invest Ophthalmol Vis Sci 2019 07;60(8):2888-2894

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States.

Purpose: Extremely preterm infants are at increased risk for retinopathy of prematurity (ROP). We previously identified several inflammatory proteins that were expressed early in life and are associated with an increased risk of ROP and several angiogenic and neurotrophic growth factors in the neonatal systemic circulation that are associated with a lower risk of ROP. In this paper, we report the results of a set of analyses designed to test the hypothesis that placental CpG methylation levels of 12 inflammation-, angiogenic-, and neurotrophic-associated genes predict the occurrence of prethreshold ROP in extremely preterm newborns.

Methods: We used placental CpG methylation data from 395 newborns from the Extremely Low Gestational Age Newborns study.

Results: Multivariable regression models revealed that placental DNA methylation of 16 CpG sites representing 8 genes were associated with prethreshold ROP. Specifically, CpG methylation in the serum amyloid A SAA1 and SAA2, brain-derived neurotrophic factor (BDNF), myeloperoxidase (MPO), C-reactive protein (CRP), angiopoietin 1 (ANGPT1), and tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) genes was associated with a lower risk of prethreshold ROP. Conversely, CpG methylation at three probes within tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and in two alternative probes within the BDNF and ANGPT1 genes was associated with an increased risk of ROP.

Conclusions: CpG methylation may be a useful marker for improving ROP prediction, opening the opportunity for early intervention to lessen disease severity.
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http://dx.doi.org/10.1167/iovs.18-26466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607927PMC
July 2019

Associations between placental CpG methylation of metastable epialleles and childhood body mass index across ages one, two and ten in the Extremely Low Gestational Age Newborns (ELGAN) cohort.

Epigenetics 2019 11 2;14(11):1102-1111. Epub 2019 Jul 2.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina , Chapel Hill , NC , USA.

The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that and early life conditions can disrupt normal fetal development and program susceptibility to later-life disease. Metastable epialleles are genomic loci in which CpG methylation patterning is responsive to maternal diet and conserved across time and tissues. Thus, these sites could serve as 'signatures' of gestational environment conditions. Here, we sought to determine if methylation of metastable epialleles was associated with changes in childhood body mass index (BMI) z-scores across ages one, two and ten in the Extremely Low Gestational Age Newborns (ELGAN) cohort. CpG methylation of 250 probes (corresponding to 111 genes) within metastable epiallele regions was measured in placental tissue. Linear mixed effects models were fit to evaluate the overall and sex-stratified associations between methylation and changes in BMI z-score over time. In total, 26 probes were associated ( < 0.05) with changes in BMI z-score overall, including probes within Mesoderm Specific Transcript and Histone Deacetylase 4 (), which have previously been associated with childhood obesity and adipogenesis. Sex-stratified analyses revealed a significant association, after adjusting for multiple comparisons ( < 0.05), within female placentas for one probe annotated to the imprinted gene PLAG1 Like Zinc Finger 1 (. These findings suggest epigenetic marks may be involved in programming susceptibility to obesity and highlight the potential to use placental tissues in predicting growth rate trajectories among premature infants.
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http://dx.doi.org/10.1080/15592294.2019.1633865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773381PMC
November 2019

Ubiquitous identification of inorganic arsenic in a cohort of second trimester amniotic fluid in women with preterm and term births.

Reprod Toxicol 2019 08 23;87:97-99. Epub 2019 May 23.

Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, University of North Carolina, United States.

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http://dx.doi.org/10.1016/j.reprotox.2019.05.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778474PMC
August 2019

Epigenome-wide DNA methylation in placentas from preterm infants: association with maternal socioeconomic status.

Epigenetics 2019 08 21;14(8):751-765. Epub 2019 May 21.

b Institute for Environmental Health Solutions, Gillings School of Global Public Health , University of North Carolina , Chapel Hill , NC , USA.

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, four 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 SES 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.
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http://dx.doi.org/10.1080/15592294.2019.1614743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615526PMC
August 2019

RNA-Sequencing of Umbilical Cord Blood to Investigate Spontaneous Preterm Birth: A Pilot Study.

AJP Rep 2019 Jan 7;9(1):e60-e66. Epub 2019 Mar 7.

Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

 To analyze the transcriptomic gene expression of umbilical cord blood leukocytes using RNA-sequencing from preterm birth (PTB) and term birth (TB).  Eight women with spontaneous PTB (sPTB) and eight women with unlabored TB were enrolled prospectively. The sPTB and TB cohorts were matched for maternal age, race, mode of delivery, and fetal sex. Cord blood RNA was extracted and a globin depletion protocol was applied, then sequenced on the Illumina HiSeq 4000. Raw read counts were analyzed with DESeq2 to test for gene expression differences between sPTB and TB.  148 genes had significant differential expression (  < 0.01). Cell cycle/metabolism gene expression was significantly higher and immune/inflammatory signaling gene expression significantly lower in the sPTB cohort compared with term. In African American (AA) infants, 18 genes specific to cell signaling, neutrophil activity, and major histocompatibility complex type 1 had lower expression in preterm compared with term cohort; the opposite pattern was seen in non-Hispanic Whites (NHWs).  Compared with term, preterm fetuses have higher cell cycle/metabolism gene expression, suggesting metabolic focus on growth and development. Immune function gene expression in this pilot study is lower in the sPTB group compared with term and differs in AA compared with NHW infants.
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http://dx.doi.org/10.1055/s-0039-1678717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406026PMC
January 2019

Disinfection Byproducts Bind Human Estrogen Receptor-α.

Environ Toxicol Chem 2019 05 20;38(5):956-964. Epub 2019 Mar 20.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Disinfection byproducts are formed during most drinking water treatment and presently number >800, some of which are implicated in human health outcomes including bladder cancer and infertility, with unknown mechanisms of action. In particular, it is not yet understood whether these compounds can disrupt the estrogen-signaling pathway through binding to the human estrogen receptor (ER). In the present study, 21 disinfection byproducts, selected for their predicted involvement in endocrine-related diseases and their structural diversity, were individually evaluated for their binding affinity to the human ER and in silico, and then a subset of these chemicals was studied in binary mixtures with the known weak estrogen, 4-n-nonylphenol. Individually, 9 of the 21 disinfection byproducts were able to weakly bind to the ER, with affinities ranging from log median inhibitory concentration values of -3.83 to -2.19 M. In binary mixtures, the chemicals followed concentration addition, with their weak binding affinities having little contribution to the overall mixture affinity. These results demonstrate the variety of small-molecule disinfection byproduct structures that are capable of binding to the ER, and that their weak binding can still be of importance when overall human exposure to mixtures of disinfection byproducts in disinfected drinking water is considered. Environ Toxicol Chem 2019;9999:1-9. © 2019 SETAC.
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http://dx.doi.org/10.1002/etc.4377DOI Listing
May 2019

Targeted Multiplex Gene Expression Profiling to Measure High-Fat Diet and Metformin Effects on Fetal Gene Expression in a Mouse Model.

Reprod Sci 2019 05 5;26(5):683-689. Epub 2018 Jul 5.

1 Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

Background: Maternal obesity and excessive gestational weight gain (GWG) are associated with delivery of a large-for-gestational-age infant. We used a high-fat diet (HFD) mouse model to separate the effect of maternal obesity from excessive GWG on fetal growth. Our objective was to identify fetal gene expression changes in an HFD and control diet (CD) mouse model with and without metformin exposure.

Study Design: Normal weight timed-pregnant (Female Friend virus B) strain mice were allocated on day e0.5 to receive HFD or CD and either plain water or metformin (2.5 mg/mL in drinking water). Dams were euthanized on day e17.5 and fetal livers harvested and frozen at -80°C. RNA was extracted and hybridized to a customized 96-gene Nanostring panel focused on angiogenesis, inflammation, and growth gene expression. Fetal liver gene expression was compared between metformin and plain water groups using analysis of variance. Significant differences in gene expression, defined by a false discovery controlled q value <0.01, were then analyzed using Ingenuity pathway analysis (IPA).

Results: In HFD-fed dams, compared to controls, the metformin-treated group had significantly lower fetal weight and 39 differentially expressed liver genes; 15 (38%) were in the growth/angiogenesis gene expression network. IPA predicted that fetal liver gene upregulation associated with metformin exposure is a result of metformin inhibition of the common upstream regulator, phosphatase and tensin homolog ( PTEN).

Conclusions: Metformin-exposed fetuses from dams fed HFD and CD have significant gene expression differences in genes specific to growth and angiogenesis pathways in the fetal liver. Diet alone did not alter fetal liver gene expression.
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http://dx.doi.org/10.1177/1933719118786453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728581PMC
May 2019

Placental CpG methylation of infants born extremely preterm predicts cognitive impairment later in life.

PLoS One 2018 7;13(3):e0193271. Epub 2018 Mar 7.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America.

Background: The placenta is the central regulator of maternal and fetal interactions. Perturbations of placental structure and function have been associated with adverse neurodevelopmental outcomes later in life. Placental CpG methylation represents an epigenetic modification with the potential to impact placental function, fetal development and child health later in life.

Study Design: Genome-wide placental CpG methylation levels were compared between spontaneous versus indicated deliveries from extremely preterm births (EPTBs) (n = 84). The association between the identified differentially methylated CpG sites and neurocognitive outcome at ten years of age was then evaluated.

Results: Spontaneous EPTB was associated with differential CpG methylation levels in 250 CpG sites (217 unique genes) with the majority displaying hypermethylation. The identified genes are known to play a role in neurodevelopment and are enriched for basic helix-loop-helix transcription factor binding sites. The placental CpG methylation levels for 17 of these sites predicted cognitive function at ten years of age.

Conclusion: A hypermethylation signature is present in DNA from placentas in infants with spontaneous EPTB. CpG methylation levels of critical neurodevelopment genes in the placenta predicted later life cognitive function, supporting the developmental origins of health and disease hypothesis (DOHaD).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841757PMC
June 2018

Long-Term Health Effects and Underlying Biological Mechanisms of Developmental Exposure to Arsenic.

Curr Environ Health Rep 2018 03;5(1):134-144

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.

Purpose Of Review: Exposure to inorganic arsenic (iAs) via drinking water represents a significant global public health threat with chronic exposure associated with cancer, skin lesions, neurological impairment, and cardiovascular diseases. Particularly susceptible populations include the developing fetus and young children. This review summarizes some of the critical studies of the long-term health effects and underlying biological mechanisms related to developmental exposure to arsenic. It also highlights the complex factors, such as the sex of the exposed individual, that contribute to susceptibility to the later life health effects of iAs.

Recent Findings: Studies in animal models, as well as human population-based studies, have established that prenatal and early life iAs exposures are associated with long-term effects, and many of these effects display sexually dimorphic responses. As an underlying molecular basis, recent epidemiologic and toxicologic studies have demonstrated that changes to the epigenome may play a key mechanistic role underlying many of the iAs-associated health outcomes. Developmental exposure to iAs results in early and later life health effects. Mechanisms underlying these outcomes are likely complex, and include disrupted key biological pathways with ties to the epigenome. This highlights the importance of continued research, particularly in animal models, to elucidate the important underpinnings (e.g., timing of exposure, metabolism, dose) of these complex health outcomes and to identify the biological mechanisms underlying sexual dimorphism in iAs-associated diseases. Future research should investigate preventative strategies for the protection from the detrimental health endpoints associated with early life exposure to iAs. Such strategies could include potential interventions focused on dietary supplementation for example the adoption of a folate-rich diet.
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http://dx.doi.org/10.1007/s40572-018-0184-1DOI Listing
March 2018

Epigenetic Regulation of the Nitric Oxide Pathway, 17-α Hydroxyprogesterone Caproate, and Recurrent Preterm Birth.

Am J Perinatol 2018 07 14;35(8):721-728. Epub 2017 Dec 14.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Objective: We sought to evaluate nitric oxide pathway placental gene expression and the epigenome (CpG methylation) among women receiving 17-α hydroxyprogesterone caproate (17-OHPC) with and without recurrent preterm birth (PTB).

Study Design: This was a case-control study. We prospectively recruited women with ≥ 1 prior singleton spontaneous PTB <34 weeks receiving 17-OHPC. DNA and RNA were isolated from placentas. RNA abundance (gene expression) and the methylome were analyzed for 84 genes in nitric oxide pathways. Women with recurrent PTB <34 weeks (cases) were compared with those delivering at term (controls). Statistical analysis included multivariable models with Bonferroni's corrected -values.

Results: In this study, 17 women met inclusion criteria; 7 preterm cases (delivered at 22.6 ± 2.9 weeks) and 10 term controls (delivered at 38.5 ± 0.8 weeks). Groups had similar PTB history, race/ethnicity, and socioeconomic risk factors for PTB. Twenty-seven nitric oxide genes displayed differential expression ( < 0.05 and  < 0.10) when comparing placentas from preterm cases and term controls; all were downregulated in preterm cases. Eight hundred sixty corresponding CpG sites were differentially methylated between the preterm cases and term controls (Bonferroni's -value <0.05).

Conclusion: CpG methylation and gene expression patterns in nitric oxide pathway genes differ among placentas from recurrent PTB compared with term birth following 17-OHPC exposure.
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http://dx.doi.org/10.1055/s-0037-1613682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002888PMC
July 2018

Microorganisms in the human placenta are associated with altered CpG methylation of immune and inflammation-related genes.

PLoS One 2017 14;12(12):e0188664. Epub 2017 Dec 14.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America.

Microorganisms in the placenta have been linked to adverse pregnancy outcomes as well as neonatal illness. Inflammation in the placenta has been identified as a contributing factor in this association, but the underlying biological mechanisms are not yet fully understood. The placental epigenome may serve as an intermediate between placental microbes and inflammation, contributing to adverse outcomes in the offspring. In the present study, genome-wide DNA methylation (n = 486,428 CpG sites) of 84 placentas was analyzed in relation to 16 species of placental microorganisms using samples collected from the Extremely Low Gestation Age Newborns (ELGAN) cohort. A total of n = 1,789 CpG sites, corresponding to n = 1,079 genes, displayed differential methylation (q<0.1) in relation to microorganisms. The altered genes encode for proteins that are involved in immune/inflammatory responses, specifically the NF-κB signaling pathway. These data support bacteria-dependent epigenetic patterning in the placenta and provide potential insight into mechanisms that associate the presence of microorganisms in the placenta to pregnancy and neonatal outcomes. This study lays the foundation for investigations of the placental microbiome and its role in placental function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188664PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730116PMC
January 2018

Toxic metals in amniotic fluid and altered gene expression in cell-free fetal RNA.

Prenat Diagn 2017 12;37(13):1364-1366

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.

Both exposures to toxic metals, as well as deficiencies in essential metals, during pregnancy has been linked to a variety of negative reproductive outcomes. The exact etiologies of such outcomes and the effects of fetal exposure to these metals are largely unknown. Therefore, the ability to assess levels of these elements is critical to determining the underlying causes of such conditions and the effects that both essential and nonessential metals have on fetal development. Thus, using cell-free fetal RNA from amniotic fluid, we set out to measure the association between amniotic fluid levels of toxic and essential metals and fetal gene expression. We find that arsenic was associated with increased expression of 3 genes known to play roles in both birth-related and reproductive effects. The results highlight the potential for detrimental health effects of prenatal metals exposure and the potential to identify biomarkers of environmental exposure during this critical developmental period.
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http://dx.doi.org/10.1002/pd.5183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766286PMC
December 2017

Identification of endocrine active disinfection by-products (DBPs) that bind to the androgen receptor.

Chemosphere 2017 Nov 22;187:114-122. Epub 2017 Aug 22.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States. Electronic address:

The formation of disinfection by-products (DBPs) in drinking water occurs when chemical disinfectants such as chlorine and chloramine react with natural organic matter and anthropogenic pollutants. Some DBPs have been linked to bladder cancer and infertility; however, the underlying mechanism of action is unknown. One possibility is disruption of the endocrine system, with DBPs binding to the androgen receptor and subsequently altering gene expression. Using the androgen receptor-binding assay and in silico molecular docking, the binding affinity of 21 suspected and known DBPs were tested individually at concentrations over the range 0.1 nM-2 mM. 14 DBPs were found to bind at IC values ranging from 1.86 mM for 2,3-dichloropropionamide to 13.5 μM for 3,4,5,6-tetrachloro-benzoquinone as compared to the positive control, 4-n-nonylphenol which bound at 31.6 μM. Since DBPs are present in drinking waters as mixtures, the question of how IC values for individual DBPs might be affected by the presence of other chemicals is addressed. Seven of the chemicals with the strongest binding affinities and one chemical with no binding affinity were tested in binary mixtures with 4-n-nonylphenol, a known androgenic chemical found in some surface waters. In these binary mixtures, concentration additive binding was observed. While typical levels of individual androgenic DBPs in drinking water are below their measured IC values, their combined binding abilities in mixtures could be a source of androgen disruption.
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http://dx.doi.org/10.1016/j.chemosphere.2017.08.105DOI Listing
November 2017

Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire.

Reprod Toxicol 2017 10 6;73:184-195. Epub 2017 Aug 6.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; Curriculum in Toxicology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

Exposure to inorganic arsenic (iAs) during pregnancy is associated with adverse health outcomes present both at birth and later in life. A biological mechanism may include epigenetic and genomic alterations in fetal genes involved in immune functioning. To investigate the role of the maternal immune response to in utero iAs exposure, we conducted an analysis of the expression of immune-related genes in pregnant women from the New Hampshire Birth Cohort Study. A set of 31 genes was identified with altered expression in association with levels of urinary total arsenic, urinary iAs, urinary monomethylated arsenic and urinary dimethylated arsenic. Notably, maternal gene expression signatures differed when stratified on fetal sex, with a more robust inflammatory response observed in male pregnancies. Moreover, the differentially expressed genes were also related to birth outcomes. These findings highlight the sex-dependent nature of the maternal iAs-induced inflammatory response in relationship to fetal outcomes.
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http://dx.doi.org/10.1016/j.reprotox.2017.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130838PMC
October 2017

Chronic early childhood exposure to arsenic is associated with a TNF-mediated proteomic signaling response.

Environ Toxicol Pharmacol 2017 Jun 8;52:183-187. Epub 2017 Apr 8.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, United States. Electronic address:

Exposure to inorganic arsenic (iAs) in drinking water is a global public health concern and is associated with a range of health outcomes, including immune dysfunction. Children are a particularly sensitive population to the effects of inorganic arsenic, yet the biological mechanisms underlying adverse health outcomes are understudied. Here we used a proteomic approach to examine the effects of iAs exposure on circulating serum protein levels in a cross-sectional children's cohort in Mexico. To identify iAs-associated proteins, levels of total urinary arsenic (U-tAs) and its metabolites were determined and serum proteins assessed for differences in expression. The results indicate an enrichment of Tumor Necrosis Factor-(TNF)-regulated immune and inflammatory response proteins that displayed decreased expression levels in relation to increasing U-tAs. Notably, when analyzed in the context of the proportions of urinary arsenic metabolites in children, the most robust response was observed in relation to the monomethylated arsenicals. This study is among the first serum proteomics assessment in children exposed to iAs.
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http://dx.doi.org/10.1016/j.etap.2017.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796657PMC
June 2017

Sexual epigenetic dimorphism in the human placenta: implications for susceptibility during the prenatal period.

Epigenomics 2017 03 17;9(3):267-278. Epub 2017 Feb 17.

Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.

Aim: Sex-based differences in response to adverse prenatal environments and infant outcomes have been observed, yet the underlying mechanisms for this are unclear. The placental epigenome may be a driver of these differences.

Methods: Placental DNA methylation was assessed at more than 480,000 CpG sites from male and female infants enrolled in the extremely low gestational age newborns cohort (ELGAN) and validated in a separate US-based cohort. The impact of gestational age on placental DNA methylation was further examined using the New Hampshire Birth Cohort Study for a total of n = 467 placentas.

Results: A total of n = 2745 CpG sites, representing n = 587 genes, were identified as differentially methylated (p < 1 × 10). The majority (n = 582 or 99%) of these were conserved among the New Hampshire Birth Cohort. The identified genes encode proteins related to immune function, growth/transcription factor signaling and transport across cell membranes.

Conclusion: These data highlight sex-dependent epigenetic patterning in the placenta and provide insight into differences in infant outcomes and responses to the perinatal environment.
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http://dx.doi.org/10.2217/epi-2016-0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331919PMC
March 2017

Neonatal Metabolomic Profiles Related to Prenatal Arsenic Exposure.

Environ Sci Technol 2017 01 20;51(1):625-633. Epub 2016 Dec 20.

RTI International, Research Triangle Park, North Carolina 27709, United States.

Prenatal inorganic arsenic (iAs) exposure is associated with health effects evident at birth and later in life. An understanding of the relationship between prenatal iAs exposure and alterations in the neonatal metabolome could reveal critical molecular modifications, potentially underpinning disease etiologies. In this study, nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was used to identify metabolites in neonate cord serum associated with prenatal iAs exposure in participants from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort, in Gómez Palacio, Mexico. Through multivariable linear regression, ten cord serum metabolites were identified as significantly associated with total urinary iAs and/or iAs metabolites, measured as %iAs, %monomethylated arsenicals (MMAs), and %dimethylated arsenicals (DMAs). A total of 17 metabolites were identified as significantly associated with total iAs and/or iAs metabolites in cord serum. These metabolites are indicative of changes in important biochemical pathways such as vitamin metabolism, the citric acid (TCA) cycle, and amino acid metabolism. These data highlight that maternal biotransformation of iAs and neonatal levels of iAs and its metabolites are associated with differences in neonate cord metabolomic profiles. The results demonstrate the potential utility of metabolites as biomarkers/indicators of in utero environmental exposure.
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http://dx.doi.org/10.1021/acs.est.6b04374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460981PMC
January 2017

miRNAs as common regulators of the transforming growth factor (TGF)-β pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia.

Food Chem Toxicol 2016 Dec 29;98(Pt A):50-57. Epub 2016 Jun 29.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, 135 Dauer Drive, CB 7431, University of North Carolina, Chapel Hill, NC, USA; Curriculum in Toxicology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria that can cause adverse health effects in both mother and fetus. There is no current cure for PE other than delivery of the fetus/placenta. While the etiology is unknown, poor placentation due to aberrant signaling of growth and angiogenic factors has been postulated as a causal factor of PE. In addition, environmental contaminants, such as the metal cadmium (Cd), have been linked to placental toxicity and increased risk of developing PE. Here, we use a translational study design to investigate genomic and epigenomic alterations in both placentas and placental trophoblasts, focused on the angiogenesis-associated transforming growth factor-beta (TGF-β) pathway. Genes within the TGF-β pathway displayed increased expression in both the preeclamptic placenta and Cd-treated trophoblasts. In addition, miRNAs that target the TGF-β pathway were also significantly altered within the preeclamptic placenta and Cd-treated trophoblasts. Integrative analysis resulted in the identification of a subset of Cd-responsive miRNAs, including miR-26a and miR-155, common to preeclamptic placentas and Cd-treated trophoblasts. These miRNAs have previously been linked to PE and are predicted to regulate members of the TGF-β pathway. Results from this study provide future targets for PE treatment.
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http://dx.doi.org/10.1016/j.fct.2016.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156314PMC
December 2016

Investigating the Role of Fetal Gene Expression in Preterm Birth.

Reprod Sci 2017 06 27;24(6):824-828. Epub 2016 Sep 27.

2 Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA.

Second-trimester amniotic fluid supernatant (AFS) contains cell-free fetal RNA (cffRNA) transcripts that can provide information about fetal gene expression. In a retrospective case-control study, we measured second-trimester fetal gene expression using cffRNA extracted from AFS in women who had spontaneous preterm birth (sPTB) <34 weeks and in women who delivered >37 weeks. We extracted cffRNA from AFS of women with singletons who had second-trimester genetic amniocenteses. Twenty-one gravidas who had sPTB and 21 term controls were matched 1:1 for maternal age, fetal sex, race, gestational age (GA) at the time of amniocentesis, and medication exposure. Cell-free fetal RNA was extracted and hybridized to a customized 65-gene NanoString panel containing genes related to oxidative stress, inflammation, and hypothalamic-pituitary-adrenal (HPA) axis and included 15 housekeeping genes. Two models were run, 1 examining sPTB in relation to case/control status and 1 examining sPTB in relation to GA as a continuous variable. Among cases, the gene expression of nitric oxide synthase 1 ( NOS1), d-aspartate oxidase ( DDO), and Beta-2-microglobulin ( B2M) was higher than controls ( P value < .05; false discovery rate-corrected Q value of ≤0.10). Nitric oxide synthase 1 and DDO are genes associated with oxidative stress; B2M is a marker of the fetal inflammatory response. Fetal HPA gene expression is not associated with GA at delivery or sPTB in second-trimester AFS. Alterations of fetal gene expression related to inflammation and oxidative stress antedate clinical symptoms and may be useful for early identification of patients at risk of having an sPTB.
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http://dx.doi.org/10.1177/1933719116670038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933097PMC
June 2017
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