Eun Jin Kwon

Prenatal exposure to perfluorinated compounds affects thyroid hormone levels in newborn girls.

Perfluorinated compounds (PFCs) are ubiquitous in the environment and have been detected in humans and wildlife. Exposure to PFCs has decreased in the United States recently, while exposure to PFCs continues in Asian countries, which represents a public health concern. Various mechanisms by which PFCs affect fetal growth have been proposed, such as activation of peroxisome proliferators, disruption of thyroid hormones and changes in lipid metabolism. However, the overall evidence for an association with thyroid hormones is not strong. Therefore, we examined the effect of various prenatal PFCs on cord blood thyroid hormones: triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH) levels, and explored the endocrine disrupting effect of these PFCs on thyroid hormone levels in children according to gender. Two hundred and seventy-nine study participants were selected from among the enrolled participants in the Ewha Birth & Growth Retrospective Cohort, a retrospective birth cohort study conducted at Ewha Womans University Hospital, Seoul, Korea between 2006 and 2010. A generalized linear model was constructed to explore the association of PFCs and thyroid hormones. Further, an analysis stratified by gender was conducted. Our study shows that cord blood perfluoro n-pentanoic acid (PFPeA) was positively associated with cord blood T4 (p=0.01) level. Gender-specific analysis showed that prenatal PFCs: PFPeA and Perfluorohexane sulfonic acid (PFHxS) exposure significantly increased T4 (p<0.01) and T3 (p=0.03), respectively, while perfluorononanoic acid (PFNA) decreased TSH (p=0.04) concentration in newborn girls. Thus, prenatal PFC exposure may disrupt thyroid hormone homeostasis. Thyroid hormones play a crucial role in fetal development and may have gender specific action. Hence, these results are of utmost importance in high-risk groups, such as pregnant women and children.

DNA methylations of MC4R and HNF4α are associated with increased triglyceride levels in cord blood of preterm infants.

AbstractThe association of preterm birth with obesity and metabolic syndrome later in life is well established. Although the biological mechanism for this association is poorly understood, epigenetic alterations of metabolic-related genes in early life may have important roles in metabolic dysfunction. Thus, we investigated the associations of DNA methylations of melanocortin 4 receptor (MC4R) and hepatocyte nuclear factor 4 alpha (HNF4&agr;) with metabolic profiles in cord blood of term and preterm infants.We measured metabolic profiles in cord blood samples of 85 term and 85 preterm infants. DNA methylation and mRNA expression levels of MC4R and HNF4&agr; in cord blood cells were quantified using pyrosequencing and real-time PCR. Triglyceride (TG) levels were grouped by percentile as low (<10th percentile), mid (11th–89th percentiles), and high (>90th percentile). A multiple linear regression model was used to assess the differential effects of DNA methylation on metabolic indices in cord blood between term and preterm infants.The beta-coefficients for associations between TG levels and methylation statuses of MC4R-CpG3 and HNF4&agr;-CpG2 in the P1 promoter differed significantly between term and preterm infants (P = 0.04 and P = 0.003, respectively). DNA methylation statuses of MC4R-CpG3 and HNF4&agr;–CpG2 in the P1 promoter were significantly lower in preterm infants in the high-TG group compared with those in the mid- and low-TG groups (P = 0.01). Notably, preterm infants in the high-TG group had higher TG levels in cord blood than term infants in the high-TG group (60.49 vs 54.57 mg/dL). In addition, MC4R and HNF4&agr; expression levels were higher in preterm infants than in term infants (P < 0.05).Epigenetic alterations of the newly identified genes MC4R and HNF4&agr; in early life might contribute to metabolic profile changes, especially increased TG levels, in the cord blood of preterm infants.

16S rRNA gene-based metagenomic analysis reveals differences in bacteria-derived extracellular vesicles in the urine of pregnant and non-pregnant women.

Recent evidence has indicated that bacteria-derived extracellular vesicles (EVs) are important for host–microbe communication. The aims of the present study were to evaluate whether bacteria-derived EVs are excreted via the urinary tract and to compare the composition of bacteria-derived EVs in the urine of pregnant and non-pregnant women. Seventy-three non-pregnant and seventy-four pregnant women were enrolled from Dankook University and Ewha Womans University hospitals. DNA was extracted from urine EVs after EV isolation using the differential centrifugation method. 16S ribosomal RNA (16S rRNA) gene sequencing was performed using high-throughput 454 pyrosequencing after amplification of the V1–V3 region of the 16S rDNA. The composition of 13 taxa differed significantly between the pregnant and non-pregnant women. At the genus level, Bacillus spp. EVs were more significantly enriched in the urine of the pregnant women than in that of the non-pregnant women (45.61% vs 0.12%, respectively). However, Pseudomonas spp. EVs were more dominant in non-pregnant women than in pregnant women (13.2% vs 4.09%, respectively). Regarding the compositional difference between pregnant women with normal and preterm delivery, EVs derived from Ureaplasma spp. and the family Veillonellaceae (including Megasphaera spp.) were more abundant in the urine of preterm-delivered women than in that of women with normal deliveries. Taken together, these data showed that Bacillus spp. EVs predominate in the urine of pregnant women, whereas Pseudomonas spp. EVs predominate in the urine of non-pregnant women; this suggests that Bacillus spp. EVs might have an important role in the maintenance of pregnancy.

Proteomic Analysis of One-carbon Metabolism-related Marker in Liver of Rat Offspring

Maternal food intake has a significant effect on the fetal environment, and an inadequate maternal diet may result in intrauterine growth restriction. Intrauterine growth restriction newborn rat pups nursed by normal diet-fed dams exhibited rapid catch-up growth, which plays a critical role in the risk for metabolic and cardiovascular disease in later life. Specifically, one-carbon metabolism in the liver plays a critical role in placental and fetal growth. Impaired functioning of one-carbon metabolism is associated with increased homocysteine levels. In this study, we applied a comprehensive proteomic approach to identify differential expression of proteins related to one-carbon metabolism in the livers of rat offspring as an effect of maternal food restriction during gestation. Data are available via ProteomeXchange with identifier PXD002578. We determined that betaine-homocysteine S-methyltransferase 1, methylenetetrahydrofolate dehydrogenase 1, and ATP synthase subunit beta mitochondrial (ATP5B) expression levels were significantly reduced in the livers of rat offspring exposed to maternal food restriction during gestation compared with in the offspring of rats fed a normal diet (p < 0.05). Moreover, the expression levels of betaine-homocysteine S-methyltransferase 1, methylenetetrahydrofolate dehydrogenase 1, and ATP synthase subunit beta mitochondrial were negatively correlated with serum homocysteine concentration in male offspring exposed to maternal food restriction during gestation and normal diet during lactation. However, in female offspring only expression levels of methylenetetrahydrofolate dehydrogenase 1 were negatively correlated with homocysteine concentration. This study shows that maternal food restriction during late gestation and normal diet during lactation lead to increased homocysteine concentration through disturbance of one-carbon metabolism in the livers of male offspring. This suggests that male offspring have an increased gender-specific susceptibility to disease in later life through fetal programming.

What is fetal programming?: a lifetime health is under the control of in utero health

The “Barker hypothesis” postulates that a number of organ structures and associated functions undergo programming during embryonic and fetal life, which determines the set point of physiological and metabolic responses that carry into adulthood. Hence, any stimulus or insult at a critical period of embryonic and fetal development can result in developmental adaptations that produce permanent structural, physiological and metabolic changes, thereby predisposing an individual to cardiovascular, metabolic and endocrine disease in adult life. This article will provide evidence linking these diseases to fetal undernutrition and an overview of previous studies in this area as well as current advances in understanding the mechanism and the role of the placenta in fetal programming.

Prenatal Exposure to Perfluorinated Compounds Affects Birth Weight Through GSTM1 Polymorphism.

Objective: The aim of this study was to investigate the effect of genetic polymorphisms on the association of prenatal exposure to perfluorinated compounds (PFCs) with birth weight. Methods: We analyzed the level of eight PFCs in cord blood and two genetic polymorphisms in maternal blood of 268 subjects. Results: Concentrations of perfluorooctanoic acid, perfluorooctane sulfonate, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) showed significant association with a decrease in birth weight (P < 0.05). In mothers with glutathione S-transferase M1 (GSTM1) null genotype, concentrations of PFNA, PFDA, and PFUnDA showed significantly negative association with birth weight (P < 0.05). Conclusion: Our findings indicated that GSTM1 polymorphism might affect the association between exposure to PFCs and birth weight, suggesting the effect of genetic susceptibility on the relationship between prenatal PFCs exposure and birth outcomes.

Differential expression and methylation of integrin subunit alpha 11 and thrombospondin in the amnion of preterm birth

Objective This study aimed to investigate the association between preterm birth and epigenetic mechanisms in the amnion. Methods We examined the association between differentially methylated regions (DMRs) and differentially expressed genes (DEG) using a cytosine-phosphate-guanine methylation array and whole-transcriptome sequencing from the amnion (preterm birth, n=5; full term, n=5). We enrolled 35 participants for mRNA expression analysis and pyrosequencing: 16 full-term and 19 preterm subjects. We compared the association of integrin subunit alpha 11 (ITGA11) and thrombospondin 2 (THBS2) gene methylation status with mRNA expression in the amnion. Results In the preterm birth group, methylation of ITGA11 and THBS2 genes was significantly lower (ITGA11 gene: 60.30% vs. 73.16%, P<0.05; THBS2 gene: 64.59% vs. 73.16%, P<0.05), and the expression of the genes was significantly higher than that in the full-term group (ITGA11 gene: 14.20 vs. 1.57, P<0.01; THBS2 gene: 1.18 vs. 10.34, P<0.05). Conclusion Methylation of the ITGA11 and THBS2 genes in the amnion was associated with preterm birth. Thus, ITGA11 and THBS2 gene methylation status in the amnion may be valuable in explaining the mechanism underlying preterm birth.

Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects

BackgroundRitodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in patients.MethodsWhole-exome sequencing of 13 subjects with serious ritodrine-induced cardiac and pulmonary side-effects was performed to identify causal genes and variants. The deleterious impact of nonsynonymous substitutions for all genes was computed and compared between cases (n = 13) and controls (n = 30). The significant genes were annotated with Gene Ontology (GO), and the associated disease terms were categorised into four functional classes for functional enrichment tests. To assess the impact of distributed rare variants in cases with side effects, we carried out rare variant association tests with a minor allele frequency ≤ 1% using the burden test, the sequence Kernel association test (SKAT), and optimised SKAT.ResultsWe identified 28 genes that showed significantly lower gene-wise deleteriousness scores in cases than in controls. Three of the identified genes—CYP1A1, CYP8B1, and SERPINA7—are pharmacokinetic genes. The significantly identified genes were categorized into four functional classes: ion binding, ATP binding, Ca2+-related, and ciliopathies-related. These four classes were significantly enriched with ciliary genes according to SYSCILIA Gold Standard genes (P < 0.01), thus representing ciliary genes. Furthermore, SKAT showed a marginal trend toward significance after Bonferroni correction with Joubert Syndrome ciliopathy genes (P = 0.05). With respect to the pharmacokinetic genes, rs1048943 (CYP1A1) and rs1804495 (SERPINA7) showed a significantly higher frequency in cases than controls, as determined by Fisher’s exact test (P < 0.05 and P < 0.01, respectively).ConclusionsRitodrine-induced cardiac and pulmonary side effects may be associated with deleterious genetic variants in ciliary and pharmacokinetic genes.