Umbilical Cord Blood Leukocytes Research Articles

In-Utero exposure to potential sources of indoor air pollution and umbilical cord blood leukocyte telomere length

Indoor air pollution (IAP) has been associated with various adverse health effects. However, the evidence regarding such an association with leukocyte telomere length (LTL) in cord blood samples is still scarce. Therefore, the present study aimed to assess the relationship between exposure to indicators of IAP and LTL in umbilical cord blood samples. This cross-sectional study was based on 188 mother-newborn pairs who participated in our study between 2020 and 2022 in Isfahan, Iran. Umbilical LTL was measured by quantitative real-time polymerase chain reaction (qRT-PCR) technique. Linear mixed-effect models were used to assess the relationship between IAP indicators and umbilical LTL, adjusted for relevant covariates. The median (interquartile range (IQR)) of umbilical LTL was 0.92 (0.47). In fully adjusted models, frequency of using degreasing spray during pregnancy (times per month) (β = −0.047, 95% CI:0.09, −0.05, P-value = 0.02), using air freshener spray during pregnancy (β = −0.26, 95% CI: −0.5, −0.02, P-value = 0.03) and frequency of using insecticides during pregnancy (times per month) (β = −0.025, 95% CI: −0.047, −0.003, P-value = 0.02) were significantly associated with shorter umbilical LTL. There was a positive significant relationship between the frequency of using cleaning spray during pregnancy (times per month) with umbilical LTL (β = 0.019, 95% CI: 0.005, 0.033, P-value = 0.01). Furthermore, the direct connection of the parking with home and the frequency of using barbecue (times per week) were marginally associated with shorter umbilical LTL. For other indicators of IAP, we did not observe any statistically significant associations. Overall, this study suggested a negative association between prenatal exposure to IAP during pregnancy and umbilical LTL.

Clinical utility of expanded NIPT for chromosomal abnormalities and etiology analysis of cytogenetic discrepancies cases.

This study is to assess the performance of expanded noninvasive prenatal testing (NIPT) in detecting chromosome aneuploidies and chromosome copy number variants (CNVs), and elucidate the discordant cases between NIPT and fetal karyotype. A total of 2139 single pregnancies have been recruited and sequenced with expanded NIPT. Karyotype analysis and CNV sequencing (CNV-seq) of amniotic fluid were performed in 22 of 23 high-risk, three low-risk NIPT pregnant women with abnormal ultrasound findings in the follow-up, and three non-reportable NIPT pregnant women. The genetic investigation of discordant results between NIPT and amniocytes in three cases was proceeded. Placental samples, fetal samples from the limb, hip, umbilical cord, and maternal peripheral blood leukocytes were collected for CNV-Seq. Expanded NIPT revealed a total of 23 positive pregnancies and yielded the overall positive predictive value (PPV) 65.2%. For T21, T18, and XXY, all the PPV was 100% respectively. For CNVs > 10Mb and 5-10Mb, the PPV was 42.8% and 16.7%, respectively. The genetic investigation of placental and fetal samples indicated different levels of placental and fetal mosaicism contributing to two of three verified discordant results. The results showed that screening for CNVs with expanded NIPT is promising although the accuracy rate remains insufficient. The different occurring time of mitotic non-disjunction of different chromosome in early development of embryo results in varying levels of chromosomal mosaicism in different placental and fetal tissues. The result highlights the significance of comprehensive cytogenetic validation of placental and fetal specimens with an inconsistent NIPT results.

DNA Methylation in Babies Born to Nonsmoking Mothers Exposed to Secondhand Smoke during Pregnancy: An Epigenome-Wide Association Study.

Background:Maternal smoking during pregnancy is related to altered DNA methylation in infant umbilical cord blood. The extent to which low levels of smoke exposure among nonsmoking pregnant women relates to offspring DNA methylation is unknown.Objective:This study sought to evaluate relationships between maternal prenatal plasma cotinine levels and DNA methylation in umbilical cord blood in newborns using the Infinium HumanMethylation 450K BeadChip.Methods:Participants from the Newborn Epigenetics Study cohort who reported not smoking during pregnancy had verified low levels of cotinine from maternal prenatal plasma (0 to ), and offspring epigenetic data from umbilical cord blood were included in this study (). Multivariable linear regression models were fit to the data, controlling for cell proportions, age, race, education, and parity. Estimates represent changes in response to any unit increase in exposure. Results:Multivariable linear regression models yielded 29,049 CpGs that were differentially methylated in relation to increases in cotinine at a 5% false discovery rate. Top CpGs were within or near genes involved in neuronal functioning (PRKG1, DLGAP2, BSG), carcinogenesis (FHIT, HSPC157) and inflammation (AGER). Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggest cotinine was related to methylation of gene pathways controlling neuronal signaling, metabolic regulation, cell signaling and regulation, and cancer. Further, enhancers associated with transcription start sites were enriched in altered CpGs. Using an independent sample from the same study population (), bisulfite pyrosequencing was performed with infant cord blood DNA for two genes within our top 20 hits (AGER and PRKG1). Results from pyrosequencing replicated epigenome results for PRKG1 (cg17079497, , , ) but not for AGER (cg09199225; , , ).Discussion:Secondhand smoke exposure among nonsmoking women may alter DNA methylation in regions involved in development, carcinogenesis, and neuronal functioning. These novel findings suggest that even low levels of smoke exposure during pregnancy may be sufficient to alter DNA methylation in distinct sites of mixed umbilical cord blood leukocytes in pathways that are known to be altered in cord blood from pregnant active smokers. https://doi.org/10.1289/EHP8099

Potential Use of Mesenchymal Multipotent Cells for Hemopoietic Stem Cell Transplantation: Pro and Contra.

The potential of mesenchymal multipotent (stem) cells (MSC) to modify immune reactions and mediate hematopoiesis boosted great interest for their use in allogeneic hemopoietic stem cell transplantation. Because of MSC production of a wide range of cytokines and growth factors, these cells are included in the therapy of graft-versus-host disease (GVHD). A number of clinical studies have demonstrated safety and efficacy of MSC-based therapy in acute GVHD. Japan and some other countries approved biomedical cell products on the base of allogeneic bone marrow (BM) MSCs as medical agents for acute GVHD treatment. Besides, MSCs may form BM stroma and improve hematopoiesis. Simultaneous transplantation of hematopoietic stem cells and MSCs effectively improved engraftment and prevented GVHD in transplantation of umbilical cord blood and human leukocyte antigens-incompatible BM stem cells. The review presents the analysis of clinical studies of MSCs in allogeneic hematopoietic stem cell transplantation and discusses different approaches for improvement of MSC-based GVHD treatment and prophylaxis.

The association of maternal psychosocial stress with newborn telomere length.

BackgroundTelomere length in early life predicts later length, and shortened telomere length among adults and children has been linked to increased risk of chronic disease and mortality. Maternal stress during pregnancy may impact telomere length of the newborn.MethodsIn a diverse cohort of 355 pregnant women receiving prenatal and delivery care services at two hospitals in San Francisco, California, we investigated the relationship between self-reported maternal psychosocial stressors during the 2nd trimester of pregnancy and telomere length (T/S ratio) in newborn umbilical cord blood leukocytes. We examined financial strain, food insecurity, high job strain, poor neighborhood quality, low standing in one’s community, experience of stressful/traumatic life events, caregiving for a dependent family member, perceived stress, and unplanned pregnancy. We used linear regression and Targeted Minimum Loss-Based Estimation (TMLE) to evaluate the change in the T/S ratio associated with exposure to each stressor controlling for maternal age, education, parity, race/ethnicity, and delivery hospital.ResultsIn TMLE analyses, low community standing (-0.09; 95% confidence interval [CI]-0.19 to 0.00) and perceived stress (-0.07; 95% CI -0.15 to 0.021 was marginally associated with shorter newborn telomere length, but the associations were not significant after adjusting for multiple comparisons. All linear regression estimates were not statistically significant. Our results also suggest that the association between some maternal stressors and newborn telomere length varies by race/ethnicity and infant sex.ConclusionsThis study is the first to examine the joint effect of multiple stressors during pregnancy on newborn TL using a flexible modeling approach.

Abstract IA23: Cadmium exposure, DNA methylation and liver cancer

Abstract Background. In the last 30 years, the incidence of hepatocellular carcinoma (HCC) has increased faster than other solid tumors and race/ethnic disparities are widening, yet suspected risk factors whose prevalence has also been on a parallel increase, cannot fully explain either this steep increase in incidence or the widening racial/ethnic gap. An understudied, yet potent risk-factor whose prevalence has been on the increase and disproportionately affects ethnic minorities, is exposure to environmental contaminants e.g., cadmium—a probable carcinogen whose main target organ is the liver. Methods. We measured cadmium concentrations in maternal blood samples obtained prenatally using inductively coupled plasma mass spectrometry. In umbilical cord blood leukocytes, we measured DNA methylation at a regulatory sequence controlling the expression of the gene cluster that includes DLK1, MEG3, MEG9, MEG8, DIO3 and some SNORD genes. Hyper-methylation at this sequence region—the first exon of MEG3—has been associated with HCC. We used zip-code level North Carolina Cancer Registry data to estimate liver cancer incidence, and Getis-Ord Gi* statistic and regression models to evaluate the relationships among cadmium exposure, MEG3 hyper-methylation and HCC incidence. Results. We found that higher cadmium concentrations were associated with significant MEG3 hypermethylation (p=0.03), and associations were specific to African Americans (p=0.01). We also found a significant geographic cluster of MEG3 hypermethylation, in the zip-code with the highest liver cancer incidence (p=0.01). ~75% of which HCC. Conclusion. Our data suggest that hypermethylation of the sequence that regulates MEG3, an established tumor suppressor is associated with cadmium exposure early life and HCC in adults. A comprehensive characterization of other networks that are altered in response to environmental exposures that disproportionately affect ethnic minorities, is urgently needed. Citation Format: Catherine Hoyo. Cadmium exposure, DNA methylation and liver cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA23.

Frequency of Cytokine Gene Polymorphism in Full-Term Newborns with Hypoxic Events

Background. An infant brain damage is an extremely urgent problem, this pathology is difficult to prevent, and subsequently it manifests itself with a variety of neurological consequences. Various mechanisms are involved in neurodamage; cytokines, as well as genes that control their activity, are under a great concern today. However, there is little data about their role as predictors of the brain damage among children after hypoxia. Aim of the research. To identify the frequency of cytokine gene polymorphism: interleukin (IL)-1β(C-511T), IL-1β(C3953T), IL-4(C589T), IL-6(C174G), IL-10(C819T), IL-10(G1082A) among newborns with hypoxic events. Materials and methods. The study involved 128 full-term newborn patients with hypoxic events: the first group (n = 48) included newborns who experienced chronic intrauterine hypoxia (CVH), the second group (n = 80) included newborns born in asphyxiation. Control group (52) included babies born without asphyxia and not suffering from CVH. A retrospective analysis of case-records was carried out. The material for molecular genetic analysis was DNA samples isolated from umbilical cord blood leukocytes using DNA Express Blood reagents (Scientific and Production Company LITECH, Moscow). Results. Compared to the control group (p = 0.03) children born in asphyxia had their T allele IL-1β (C-511T) prevailed. The group of newborn who had CVH had their TT genotype (p = 0.04) and the T IL-1β allele (C-511T) (p = 0.01) prevailed compared to the control group. In the same study group while studying the polymorphism of the IL-1β gene, the T allele (p = 0.03) at the point C3953T prevailed, in contrast to the control group. Conclusion. Due to the fact that cytokines are part of a reaction cascade leading to the secondary brain damage, under the action of hypoxia, it was found that among newborns undergoing asphyxia and chronic intrauterine hypoxia the increased frequencies of carriage of IL-1β-511TT and IL-1β-3953TT genotypes, and IL-1β-511T and IL-1β-3953T alleles increase the risk of neurodamage.

Trimester-Specific Associations of Prenatal Lead Exposure With Infant Cord Blood DNA Methylation at Birth.

Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within PDGFRL associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within TRHR with tibia bone Pb (adjusted P-value < .05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted P-value < .05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific.

Maternal environmental exposure to bisphenols and epigenome-wide DNA methylation in infant cord blood.

Maternal prenatal exposures, including bisphenol A (BPA), are associated with offspring’s risk of disease later in life. Alterations in DNA methylation may be a mechanism through which altered prenatal conditions (e.g. maternal exposure to environmental toxicants) elicit this disease risk. In the Michigan Mother and Infant Pairs Cohort, maternal first-trimester urinary BPA, bisphenol F, and bisphenol S concentrations were tested for association with DNA methylation patterns in infant umbilical cord blood leukocytes (N = 69). We used the Illumina Infinium MethylationEPIC BeadChip to quantitatively evaluate DNA methylation across the epigenome; 822 020 probes passed pre-processing and quality checks. Single-site DNA methylation and bisphenol models were adjusted for infant sex, estimated cell-type proportions (determined using cell-type estimation algorithm), and batch as covariates. Thirty-eight CpG sites [false discovery rate (FDR) <0.05] were significantly associated with maternal BPA exposure. Increasing BPA concentrations were associated with lower DNA methylation at 87% of significant sites. BPA exposure associated DNA methylation sites were enriched for 38 pathways significant at FDR <0.05. The pathway or gene-set with the greatest odds of enrichment for differential methylation (FDR <0.05) was type I interferon receptor binding. This study provides a novel understanding of fetal response to maternal bisphenol exposure through epigenetic change.

Prenatal cadmium exposure is associated with shorter leukocyte telomere length in Chinese newborns

BackgroundNewborn telomere length (TL) is considered a potential marker for future disease and lifelong health, but few epidemiological studies have examined the determinants of TL in early life. The study aim was to investigate whether there is an association between prenatal cadmium exposure and relative cord blood TL in Chinese newborns.MethodsParticipants were 410 mother–newborn pairs drawn from a prospective birth cohort study conducted in Wuhan, China, between November 2013 and March 2015. Urine samples were collected from pregnant women during their period of institutional delivery. Urinary cadmium concentrations were measured by inductively coupled plasma mass spectrometry. The real-time quantitative polymerase chain reaction detection was used to measure relative TL using genomic DNA isolated from umbilical cord blood leukocytes. Multivariate linear regression models were used to estimate the effect of prenatal urinary cadmium concentration on relative cord blood TL.ResultsThe geometric mean of maternal urinary cadmium concentration was 0.68 μg/g creatinine. In the multivariate-adjusted linear regression model, per doubling of maternal urinary cadmium concentration was associated with 6.83% (95% CI − 11.44%, − 1.97%; P = 0.006) shorter relative cord blood TL. Stratified analyses indicated that the inverse association between prenatal urinary cadmium and newborn relative TL was more pronounced among female infants and mothers < 29 years, while there were no significant effect modification according to infant sex (P for interaction = 0.907) and maternal age (P for interaction = 0.797).ConclusionsThe findings indicated that increased maternal urinary cadmium was associated with shortened relative cord blood TL. The results provide more evidence of the negative effects of environmental cadmium exposure and suggest that accelerated aging or cadmium-related diseases may begin in early life.

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

Objective To analyze the transcriptomic gene expression of umbilical cord blood leukocytes using RNA-sequencing from preterm birth (PTB) and term birth (TB). Study Design 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. Results 148 genes had significant differential expression ( q < 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). Conclusion 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.

Measures of Maternal Psycho-Social Stress and Biomarkers of Stress Response in the Maternal-Fetal Unit

In a cohort of 500 pregnant women recruited from two San Francisco hospitals serving economically and ethnically diverse populations, we used Targeted Minimum Loss-Based Estimation (TMLE) to evaluate the association between perceptual measures of maternal psycho-social stress and two biological measures of stress response: 1) telomere length (TL) in umbilical cord blood leukocytes collected at delivery, and 2) corticotropin-releasing hormone (CRH) in maternal plasma collected during the 2nd trimester. We evaluated ten dimensions of maternal stress, derived from questionnaires: job-related, neighborhood, community standing, experience of racism, perceived stress, acute stressful events, depression, pregnancy satisfaction, nativity, and material deprivation. All domains were identified as important predictors of TL/CRH in non-parametric variable important analyses. Therefore, CRH analyses included all stressors and were adjusted for pregnancy complications, mother&amp;#8217;s age, parity, and race/ethnicity. TL analyses were additionally adjusted for infant sex, and gestational age at birth. 30% of participants identified as Latina, 7% Black, 40% White, 16% Asian, and 7% identified as other/mixed. Less than 10% of women did not complete high-school and 60% had a bachelor&amp;#8217;s degree or higher. Biologic factors were more important at predicting TL than stress. Conversely, stress was more important at predicting CRH than biological factors. Counter-intuitively, experiencing racism (0.15, 95% CI: 0.12-0.17) and perceived stress (0.24, 95% CI: 0.21-0.27) were associated with greater TL (expressed as the relative ratio of telomere repeat copy number to single-copy gene copy number or T/S ratio). Pregnancy complications were associated with elevated CRH (0.13, 95% CI: -0.02-0.28), while pregnancy dissatisfaction was associated with lower CRH (-0.15, 95% CI: -0.30-0.01). Results suggest complex relationships between perceived stress and response biomarkers in the maternal-fetal unit.

Association between Exposure to Per- and Polyfluoroalkyl Substances (PFAS) during Pregnancy and Biomarkers of Stress Response in the Maternal-Fetal Unit

In a demographically diverse cohort of 500 pregnant women recruited from two San Francisco hospitals, we used linear regression to evaluate the association between eight PFAS with detection frequency of 50% or greater in our sample, and two biological measures of stress response: 1) telomere length (TL) in umbilical cord blood leukocytes collected at delivery, and 2) corticotropin-releasing hormone (CRH) in maternal plasma collected during the 2nd trimester. Both outcomes were log-transformed. PFAS levels (ug/L) were measured in mother&amp;#8217;s serum during the 2nd trimester, and also log-transformed. Each chemical was assessed separately since levels were highly correlated. CRH analyses were adjusted for pregnancy complications, mother&amp;#8217;s age, parity, and race/ethnicity. TL analyses were additionally adjusted for infant sex, and gestational age at birth. We also evaluated the associations separately for Latina and White women.The burden of PFAS exposure was greater among Latinas (30% of participants) than White women (40% of participants) in our study population. PFAS were not associated with TL, expressed as the relative ratio of telomere repeat copy number to single-copy gene copy number. A one unit increase in Perfluoroundecanoic acid (PFUdA) was associated with a 0.14 increase in CRH in race adjusted models (95% CI: 0.04&amp;#8211;0.23). Higher levels of Perfluorononanoic acid (PFNA; 0.25, 95% CI: 0.07-0.44), Perfluorooctanesulfonic acid (PFOS; 0.161, 95% CI: 0.003-0.32), 2-(N-Methyl-perfluorooctane sulfonamido) acetic acid (MePFOSAAchOH; 0.18, 95% CI: 0.03-0.34), Perfluorohexane sulfonic acid (PFHxS; 0.20, 95% CI: 0.02-0.38), and PFUdA (0.38, 95% CI: 0.19&amp;#8211;0.57) were all significantly associated with higher CRH among Latinas. Higher levels of Perfluorooctanesulfonamide (PFOSA; 0.07, 95% CI: 0.01-0.15) were significantly associated with higher CRH among white women. Results suggest complex relationships between prenatal PFAS exposure and stress response biomarkers.

Associations between imprinted gene differentially methylated regions, appetitive traits and body mass index in children.

Knowledge regarding genetic influences on eating behaviours is expanding; yet less is known regarding contributions of epigenetic variation to appetitive traits and body mass index (BMI) in children. The purpose of this study was to explore relationships between methylation at differentially methylated regions (DMRs) of imprinted genes (insulin-like growth factor 2/H19 and Delta-like, Drosophila, homolog 1/maternally expressed gene 3) using DNA extracted from umbilical cord blood leucocytes, two genetically influenced appetitive traits (food responsiveness and satiety responsiveness) and BMI. Data were obtained from participants (N=317; mean age=3.6years; SD=1.8years) from the Newborn Epigenetic STudy. Conditional process models were implemented to investigate the associations between DMRs of imprinted genes and BMI, and test whether this association was mediated by appetitive traits and birthweight and moderated by sex. Appetitive traits and birthweight did not mediate the relationship between methylation at DMRs. Increased insulin-like growth factor 2 DMR methylation was associated with higher satiety responsiveness. Higher satiety responsiveness was associated with lower BMI. Associations between methylation at DMRs, appetitive traits and BMI differed by sex. This is one of the first studies to demonstrate associations between epigenetic variation established prior to birth with appetitive traits and BMI in children, providing support for the need to uncover genetic and epigenetic mechanisms for appetitive traits predisposing some individuals to obesity.

Racial differences in maternal and umbilical cord blood leukocyte telomere length and their correlations.

Telomere length at birth sets the baseline for telomere shortening and may influence adult disease risk like cancer. Telomere length is heritable, but may also be a marker of exposures in utero, including those influencing racial differences in risk. We examined racial differences in telomere length in maternal and umbilical cord blood from male neonates, and maternal-neonate correlations to generate hypotheses. Black and white pregnant women were recruited in 2006-2007 and followed to postpartum. Data came from questionnaires and medical records. Relative telomere length was measured by qPCR in leukocyte DNA. We estimated mean telomere length in mothers and neonates (n = 55 pairs) using linear regression and maternal-cord blood Spearman correlations, overall and by race. Black mothers had shorter age- and plate-adjusted telomere length (2.49, 95% CI 2.11-2.86) than whites (2.92, 95% CI 2.63-3.22; p = 0.1) and black neonates had shorter telomere length (2.58, 95% CI 2.16-3.01) than whites (3.13, 95% CI 2.79-3.47; p = 0.1), though not statistically significant. Differences were attenuated after further adjustment for maternal factors. Maternal-cord blood correlations were moderate (r = 0.53, p < 0.0001), and did not differ by race. Telomere length may differ by race at birth due to both inherited and racial differences in maternal factors. This study was for hypothesis generation and results should be followed up in larger studies.

DNA methylation of imprinted genes at birth is associated with child weight status at birth, 1\xa0year, and 3\xa0years

BackgroundThis study assessed the associations between nine differentially methylated regions (DMRs) of imprinted genes in DNA derived from umbilical cord blood leukocytes in males and females and (1) birth weight for gestational age z score, (2) weight-for-length (WFL) z score at 1 year, and (3) body mass index (BMI) z score at 3 years.MethodsWe conducted multiple linear regression in n = 567 infants at birth, n = 288 children at 1 year, and n = 294 children at 3 years from the Newborn Epigenetics Study (NEST). We stratified by sex and adjusted for race/ethnicity, maternal education, maternal pre-pregnancy BMI, prenatal smoking, maternal age, gestational age, and paternal race. We also conducted analysis restricting to infants not born small for gestational age.ResultsWe found an association between higher methylation of the sequences regulating paternally expressed gene 10 (PEG10) and anthropometric z scores at 1 year (β = 0.84; 95% CI = 0.34, 1.33; p = 0.001) and 3 years (β = 1.03; 95% CI = 0.37, 1.69; p value = 0.003) in males only. Higher methylation of the DMR regulating mesoderm-specific transcript (MEST) was associated with lower anthropometric z scores in females at 1 year (β = − 1.03; 95% CI − 1.60, − 0.45; p value = 0.001) and 3 years (β = − 1.11; 95% CI − 1.98, − 0.24; p value = 0.01). These associations persisted when we restricted to infants not born small for gestational age.ConclusionOur data support a sex-specific association between altered methylation and weight status in early life. These methylation marks can contribute to the compendium of epigenetically regulated regions detectable at birth, influencing obesity in childhood. Larger studies are required to confirm these findings.

OP 54 Early- and late-onset preeclampsia and the tissue-specific epigenome of the placenta and newborn

Introduction Preeclampsia (PE) carries increased risks of cardiovascular- and metabolic diseases in mothers and offspring during the life course. While the severe early-onset PE (EOPE) phenotype originates from impaired placentation in early pregnancy, late-onset PE (LOPE) is in particular associated with pre-existing maternal cardiovascular- and metabolic risk factors. We hypothesize that PE is associated with altered epigenetic programming of placental and fetal tissues and that these epigenetic changes link both PE phenotypes with features of cardiovascular- and metabolic diseases in offspring. Objectives In this study we examined tissue-specific genome-wide DNA methylation of umbilical cord blood leucocytes (UC-WBC), placental tissue and human umbilical cord endothelial cells (HUVEC) in relation to EOPE and LOPE. Patients and methods A nested case-control study was conducted in The Rotterdam Periconceptional Cohort (Predict study) comprising 13 EOPE, 16 LOPE, and three control groups of 36 uncomplicated pregnancies, 27 normotensive fetal growth restricted and 20 normotensive preterm birth (PTB) complicated pregnancies. Placental tissue, UC-WBC and HUVEC were collected and DNA methylation of cytosine-guanine dinucleotides was measured by the Illumina HumanMethylation450K BeadChip. An epigenome-wide analysis was performed by using multiple linear regression models. Results Epigenome-wide analysis revealed significant differences only between tissues from EOPE and PTB controls, with 5001 mostly hypermethylated differentially methylated positions (DMPs) in UC-WBC and 869 mostly hypomethylated DMPs in placental tissue, situated in or close to genes associated with cardiovascular system developmental pathways. (Fig. 1. Density plot of β -values per tissue and per group). (Fig. 2. Heatmap based on clustering of methylation ( β -value) of all differentially methylated CpGs). Conclusion This study shows differential methylation in UC-WBC and placental tissue in EOPE as compared to PTB, identifying DMPs that are associated with cardiovascular system pathways. Future studies should examine these loci and pathways in more detail to elucidate the associations between prenatal PE exposure and the cardiovascular disease risk in offspring. Download : Download high-res image (160KB) Download : Download full-size image Download : Download high-res image (215KB) Download : Download full-size image

DNA Methylation of Regulatory Regions of Imprinted Genes at Birth and Its Relation to Infant Temperament.

BACKGROUNDDNA methylation of the differentially methylated regions (DMRs) of imprinted genes is relevant to neurodevelopment.METHODSDNA methylation status of the DMRs of nine imprinted genes in umbilical cord blood leukocytes was analyzed in relation to infant behaviors and temperament (n = 158).RESULTSMEG3 DMR levels were positively associated with internalizing (β = 0.15, P = 0.044) and surgency (β = 0.19, P = 0.018) behaviors, after adjusting for birth weight, gender, gestational age at birth, maternal age at delivery, race/ethnicity, education level, smoking status, parity, and a history of anxiety or depression. Higher methylation levels at the intergenic MEG3-IG methylation regions were associated with surgency (β = 0.28, P = 0.0003) and PEG3 was positively related to externalizing (β = 0.20, P = 0.01) and negative affectivity (β = 0.18, P = 0.02).CONCLUSIONWhile the small sample size limits inference, these pilot data support gene-specific associations between epigenetic differences in regulatory regions of imprinted domains at birth and later infant temperament.

Influence of In Utero Maternal and Neonate Factors on Cord Blood Leukocyte Telomere Length: Clues to the Racial Disparity in Prostate Cancer?

Background. Modifiable factors in adulthood that explain the racial disparity in prostate cancer have not been identified. Because racial differences in utero that may account for this disparity are understudied, we investigated the association of maternal and neonate factors with cord blood telomere length, as a cumulative marker of cell proliferation and oxidative damage, by race. Further, we evaluated whether cord blood telomere length differs by race. Methods. We measured venous umbilical cord blood leukocyte relative telomere length by qPCR in 38 black and 38 white full-term male neonates. Using linear regression, we estimated geometric mean relative telomere length and tested for differences by race. Results. Black mothers were younger and had higher parity and black neonates had lower birth and placental weights. These factors were not associated with relative telomere length, even after adjusting for or stratifying by race. Relative telomere length in black (2.72) and white (2.73) neonates did not differ, even after adjusting for maternal or neonate factors (all p > 0.9). Conclusions. Maternal and neonate factors were not associated with cord blood telomere length, and telomere length did not differ by race. These findings suggest that telomere length at birth does not explain the prostate cancer racial disparity.

Maternal cadmium, iron and zinc levels, DNA methylation and birth weight.

BackgroundCadmium (Cd) is a ubiquitous and environmentally persistent toxic metal that has been implicated in neurotoxicity, carcinogenesis and obesity and essential metals including zinc (Zn) and iron (Fe) may alter these outcomes. However mechanisms underlying these relationships remain limited.MethodsWe examined whether maternal Cd levels during early pregnancy were associated with offspring DNA methylation at regulatory sequences of genomically imprinted genes and weight at birth, and whether Fe and Zn altered these associations. Cd, Fe and Zn were measured in maternal blood of 319 women ≤12 weeks gestation. Offspring umbilical cord blood leukocyte DNA methylation at regulatory differentially methylated regions (DMRs) of 8 imprinted genes was measured using bisulfite pyrosequencing. Regression models were used to examine the relationships among Cd, Fe, Zn, and DMR methylation and birth weight.ResultsElevated maternal blood Cd levels were associated with lower birth weight (p = 0.03). Higher maternal blood Cd levels were also associated with lower offspring methylation at the PEG3 DMR in females (β = 0.55, se = 0.17, p = 0.05), and at the MEG3 DMR in males (β = 0.72, se = 0.3, p = 0.08), however the latter association was not statistically significant. Associations between Cd and PEG3 and PLAGL1 DNA methylation were stronger in infants born to women with low concentrations of Fe (p < 0.05).ConclusionsOur data suggest the association between pre-natal Cd and offspring DNA methylation at regulatory sequences of imprinted genes may be sex- and gene-specific. Essential metals such as Zn may mitigate DNA methylation response to Cd exposure. Larger studies are required.