Early post-conception maternal cortisol, children’s HPAA activity and DNA methylation profiles

2018 ◽  
Vol 10 (1) ◽  
pp. 73-87 ◽  
Author(s):  
C. K. Barha ◽  
K. G. Salvante ◽  
M. J. Jones ◽  
P. Farré ◽  
J. Blais ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Critical Role ◽  
Cpg Sites ◽  
School Year ◽  
Specimen Collection ◽  
Buccal Epithelial Cells ◽  
Health And Disease ◽  
Cortisol Responses ◽  
Pituitary Adrenal Axis ◽  
Experimental Challenge

AbstractThe hypothalamic–pituitary–adrenal axis (HPAA) plays a critical role in the functioning of all other biological systems. Thus, studying how the environment may influence its ontogeny is paramount to understanding developmental origins of health and disease. The early post-conceptional (EPC) period could be particularly important for the HPAA as the effects of exposures on organisms’ first cells can be transmitted through all cell lineages. We evaluate putative relationships between EPC maternal cortisol levels, a marker of physiologic stress, and their children’s pre-pubertal HPAA activity (n=22 dyads). Maternal first-morning urinary (FMU) cortisol, collected every-other-day during the first 8 weeks post-conception, was associated with children’s FMU cortisol collected daily around the start of the school year, a non-experimental challenge, as well as salivary cortisol responses to an experimental challenge (all Ps<0.05), with some sex-related differences. We investigated whether epigenetic mechanisms statistically mediated these links and, therefore, could provide cues as to possible biological pathways involved. EPC cortisol was associated with >5% change in children’s buccal epithelial cells’ DNA methylation for 867 sites, while children’s HPAA activity was associated with five CpG sites. Yet, no CpG sites were related to both, EPC cortisol and children’s HPAA activity. Thus, these epigenetic modifications did not statistically mediate the observed physiological links. Larger, prospective peri-conceptional cohort studies including frequent bio-specimen collection from mothers and children will be required to replicate our analyses and, if our results are confirmed, identify biological mechanisms mediating the statistical links observed between maternal EPC cortisol and children’s HPAA activity.

scholarly journals Genome-wide DNA methylation can identify preterm birth-related genes in maternal blood

2020 ◽  
Author(s):  
Young-Ah You ◽  
Eun Jin Kwon ◽  
Han-Sung Hwang ◽  
Suk-Joo Choi ◽  
Sae Kyung Choi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Preterm Birth ◽  
Maternal Blood ◽  
Differential Methylation ◽  
Multiple Tests ◽  
Cpg Sites ◽  
Genome Wide ◽  
Increased Risk ◽  
Health And Disease ◽  
Whole Blood Cells

Abstract Background Preterm birth is associated with an increased risk of neonatal complications and death, as well as poor health and disease later in life. Epigenetics could contribute to the mechanism underlying preterm birth. Results Genome-wide DNA methylation in whole blood cells from ten women was assessed using Illumina Infinium HumanMethylation450 BeadChips array. We identified 6,755 differentially methylated CpG sites between term and preterm birth. Although no differential methylation of these CpGs were found in correcting for multiple tests, seven VTRNA2-1 CpGs in promotor region of island were detected in top different methylation. We performed pyrosequencing validation with blood samples from the pregnant women. The methylation levels of VTRNA2-1 were either low (hypomethylated, 0–12.2%) or high (hypermethylated, 32.6–50.8%). Hypermethylation of VTRNA2-1 was associated with an increased risk of preterm birth after adjusting for maternal age, delivered season, parity and count of white blood cell. The mRNA expression of VTRNA2-1 was 0.51-fold lower in PTB delivered women compared with women with term deliveries. Conclusion This study suggests that change of VTRNA2-1 methylation is related to PTB in maternal blood. Further elucidate to underlay mechanisms of preterm birth and affect to future systems biology studies to predict preterm birth.

scholarly journals Prenatal smoke effect on mouse offspring Igf1 promoter methylation from fetal stage to adulthood is organ and sex specific

2020 ◽  
Vol 318 (3) ◽  
pp. L549-L561
Author(s):  
Zhijun Zeng ◽  
Karolin F. Meyer ◽  
Khosbayar Lkhagvadorj ◽  
Wierd Kooistra ◽  
Marjan Reinders-Luinge ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Methylation ◽  
Large Scale ◽  
Developmental Stages ◽  
Association Studies ◽  
Inverse Correlation ◽  
Cpg Sites ◽  
Increased Risk ◽  
Organ Specific ◽  
Health And Disease

Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development, and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome-wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF1) is important in growth, differentiation, and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for 2 persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex specific. The PSE effect was less pronounced in adult offspring compared with the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared with the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when the data of all three stages were combined. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming, which supports the developmental origins of health and disease (DOHaD) hypothesis.

scholarly journals Genetic and environmental determinants of variation in the plasma lipidome of older Australian twins

2020 ◽  
Author(s):  
Matthew W.K. Wong ◽  
Anbupalam Thalamuthu ◽  
Nady Braidy ◽  
Karen A. Mather ◽  
Yue Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Blood Lipids ◽  
Plasma Lipids ◽  
Critical Role ◽  
Genetic Regulation ◽  
Environmental Influences ◽  
Disease States ◽  
Twin Model ◽  
Gene Transcripts ◽  
Health And Disease

AbstractThe critical role of blood lipids in a broad range of health and disease states is well recognised, while an understanding of the complex genetic regulation of lipid homeostasis is emerging. Traditional blood lipids (LDL-C, HDL-C and triglycerides) are known to be substantially regulated by genetic variation. Less well explored is the interplay of genetics and environment within the broader blood lipidome. Here we use the twin model to examine heritability of the plasma lipidome among healthy older aged twins and explore gene expression and epigenetic (DNA methylation) associations of these lipids. Heritability of 209 plasma lipids quantified by liquid chromatography coupled mass spectrometry (LC-MS) was assessed in 75 monozygotic and 55 dizygotic twin pairs enrolled in the Older Australian Twins Study (OATS), aged 69-93 years. Only 27/209 lipids (13.3%) were significantly heritable under the classical ACE twin model (h2 = 0.28-0.59). Ceramides (Cer) and triglycerides (TG) were most heritable, while sphingomyelins (SM) and most phospholipids, especially lysophospholipids, were not significantly heritable. Lipid levels correlated with 3731 transcripts. Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, which were not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for a proportion of variability in some non-heritable lipids, especially lysophosphatidylcholine (LPC). We found a complex interplay of genetic and environmental influences on the ageing plasma lipidome, with most of the variation controlled by unique environmental influences.

scholarly journals Genetic and environmental determinants of variation in the plasma lipidome of older Australian twins

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Matthew WK Wong ◽  
Anbupalam Thalamuthu ◽  
Nady Braidy ◽  
Karen A Mather ◽  
Yue Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Blood Lipids ◽  
Critical Role ◽  
Complex Interplay ◽  
Disease States ◽  
Twin Model ◽  
Genome Wide ◽  
Gene Transcripts ◽  
Health And Disease

The critical role of blood lipids in a broad range of health and disease states is well recognised but less explored is the interplay of genetics and environment within the broader blood lipidome. We examined heritability of the plasma lipidome among healthy older-aged twins (75 monozygotic/55 dizygotic pairs) enrolled in the Older Australian Twins Study (OATS) and explored corresponding gene expression and DNA methylation associations. 27/209 lipids (13.3%) detected by liquid chromatography-coupled mass spectrometry (LC-MS) were significantly heritable under the classical ACE twin model (h2 = 0.28–0.59), which included ceramides (Cer) and triglycerides (TG). Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for variability in some non-heritable lipids. We reveal a complex interplay of genetic and environmental influences on the ageing plasma lipidome.

scholarly journals M210. GRIN2B METHYLATION IS RELATED TO PANSS EXCITED COMPONENT (PANSS-EC) IN SCHIZOPHRENIA

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S216-S216
Author(s):  
Helene Fachim ◽  
Olga Yu Fedorenko ◽  
Elena G Kornetova ◽  
Svetlana A Ivanova ◽  
Adrian Heald ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Critical Role ◽  
Glutamatergic System ◽  
Cpg Sites ◽  
Psychiatric Disturbances ◽  
Syndrome Scale ◽  
Symptom Response ◽  
Antipsychotic Drug Treatment ◽  
Relationship Of ◽  
Specific Symptoms

Abstract Background Among the adversities found in schizophrenia, the dysfunctions in the glutamatergic system, specifically the N-methyl-D-aspartate receptor (NMDAR) are apparent. GRIN2B (coding a NMDAR subunit) has a critical role in synaptic plasticity and important participation in CNS neurodevelopment, this gene is closely associated with behavioural and cognitive impairments. One of the mechanisms that may underlie the deficiencies seen in the glutamatergic system in psychosis is DNA methylation as it is known to regulate gene expression. As part of a major study investigating the relationship of DNA methylation with schizophrenia and its symptom response to antipsychotic drug treatment, we determined whether methylation of the GRIN2B promoter region was associated with specific symptoms of schizophrenia determined by the Positive and Negative Syndrome Scale (PANSS). Methods Blood samples were collected from schizophrenia patients (n = 79) on admission to the study. Bisulphite conversion and pyrosequencing were used to determine methylation levels in 5 CpG sites in the GRIN2B promoter. PANSS score and the five factor subscores (Wallwork et al, 2012) at baseline and at 6 weeks was collected, and the change in PANSS following treatment was determined. Results Mean methylation at the five CpG sites was not associated with overall PANSS score or with the change in PANSS. However, a highly significant positive correlation of mean methylation with the baseline excited factor score (r=0.342, p=0.002), but with no other PANSS subscore, was found. No significant correlation with changes in PANSS, or in changes in subscores, over the treatment period was found. Discussion This is the first evidence showing GRIN2B methylation correlation with the excited component (EC) of schizophrenia symptoms. PANSS-EC is used to assess agitated patients (Lindenmayer et al., 2008, Montoya et al., 2011), and is valuable in identifying risks associated with agitation and aggression related to primary psychiatric disturbances. This result suggests that this GRIN2B epigenetic signature may relate to agitation and aggressive behaviour in schizophrenia.

scholarly journals Genetically Predicted Levels of DNA Methylation Biomarkers and Breast Cancer Risk: Data From 228 951 Women of European Descent

2019 ◽  
Vol 112 (3) ◽  
pp. 295-304 ◽  
Author(s):  
Yaohua Yang ◽  
Lang Wu ◽  
Xiao-Ou Shu ◽  
Qiuyin Cai ◽  
Xiang Shu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Statistical Power ◽  
Prediction Models ◽  
Statistical Tests ◽  
Critical Role ◽  
White Blood Cells ◽  
Cpg Sites

Abstract Background DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. Methods Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women’s Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided. Results Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10–7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. Conclusion Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.

The Laryngeal Epithelium in Reflux

2011 ◽  
Vol 21 (3) ◽  
pp. 112-117 ◽  
Author(s):  
Elizabeth Erickson-Levendoski ◽  
Mahalakshmi Sivasankar
Keyword(s):  
Laryngopharyngeal Reflux ◽  
Critical Role ◽  
Structure And Function ◽  
Laryngeal Disease ◽  
Health And Disease ◽  
And Function ◽  
The Impact

The epithelium plays a critical role in the maintenance of laryngeal health. This is evident in that laryngeal disease may result when the integrity of the epithelium is compromised by insults such as laryngopharyngeal reflux. In this article, we will review the structure and function of the laryngeal epithelium and summarize the impact of laryngopharyngeal reflux on the epithelium. Research investigating the ramifications of reflux on the epithelium has improved our understanding of laryngeal disease associated with laryngopharyngeal reflux. It further highlights the need for continued research on the laryngeal epithelium in health and disease.

EPIGENETIC ALTERATIONS ASSOCIATED WITH PREMATURE OVARIAN FAILURE

2008 ◽  
Vol 31 (4) ◽  
pp. 11
Author(s):  
Manda Ghahremani ◽  
Courtney W Hannah ◽  
Maria Peneherrera ◽  
Karla L Bretherick ◽  
Margo R Fluker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Premature Ovarian Failure ◽  
Promoter Region ◽  
Gene Promoter ◽  
Ovarian Failure ◽  
P Value ◽  
Epigenetic Alterations ◽  
Methylation Array ◽  
Cpg Sites ◽  
Deficient Mice

Background/Purpose: Premature ovarian failure (POF) affects 1% of women with a largely idiopathic and poorly understood etiology. The objective of this study was to identify specific epigenetic alterations by measuring DNA methylation of gene regulatory regions in women with POF vs. controls. Methods: Blood samples were collected from idiopathic POFpatients (Amenorrhea for at least 3 months and 2 serum FSH levels of > 40mIU/ml obtained > 1 month apart prior to age 40) and control women (CW) (healthy pregnancy after age 37 with out a pregnancy loss). Genomic DNA was extracted from EDTA anticoagulated blood and bisulfite converted for analysis using the Illumina Golden Gate Methylation Panel which measures DNA methylation at 1506 CpG sites in the promoter regions of 807 genes in 10 POF and 12 CW. Candidate genes with altered epigenetic marks between POF and CW at a nominal P-value < 0.05 were identified using a t-testcomparison within the Illumina bead studio software. Genes of interest were further analyzed for quantitative methylation at specific CpG sites using pyrosequencing in 30 POF and 30 CW. Results: Comparison of DNA methylation profiles of our initial POF and CW groups identified several genes with statistically significanthyper- or hypo- methylation in the POF group (P < 0.05), including the Androgen Receptor (AR)promoter region, which was significantly hypermethylated. To further validate these results, DNA methylation of the AR gene promoter was quantified bypryosequencing in a larger group of POF and CW. Pyrosequencing further confirmed a significantly higher DNA methylation of the AR promoter region inPOF vs. CW (P=0.007). Conclusions: This is a novel study identifying epigenetic alterations in POF. The hypermethylation of the AR gene in POF patients may cause decreased level of the AR in these women. This is especially interesting given a recent report of induced POF in AR deficient mice^1. Specific epigenetic markers, as identified by DNA methylation array profiling in blood, may serve as useful biomarkers for POF and other fertility disorders. However, it will need to be determined if these methylation changes are present prior to diagnosis, or are a consequence of menopause itself. Reference: 1.Hiroko S. et al. Premature ovarian failure in androgenreceptor deficient mice. PNAS;103:224-9

Epigenetics, Nutrition, Disease and Drug Development

2019 ◽  
Vol 16 (4) ◽  
pp. 386-391 ◽  
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Dna Methylation ◽  
Drug Discovery ◽  
Rna Interference ◽  
Nutritional Requirements ◽  
Signal Pathways ◽  
Disease Development ◽  
Epigenetic Mechanisms ◽  
Epigenetic Changes ◽  
Health And Disease ◽  
Novel Drug

Epigenetic mechanisms comprising of DNA methylation, histone modifications and gene silencing by RNA interference have been strongly linked to the development and progression of various diseases. These findings have triggered research on epigenetic functions and signal pathways as targets for novel drug discovery. Dietary intake has also presented significant influence on human health and disease development and nutritional modifications have proven important in prevention, but also the treatment of disease. Moreover, a strong link between nutrition and epigenetic changes has been established. Therefore, in attempts to develop novel safer and more efficacious drugs, both nutritional requirements and epigenetic mechanisms need to be addressed.

scholarly journals DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aya Sasaki ◽  
Margaret E. Eng ◽  
Abigail H. Lee ◽  
Alisa Kostaki ◽  
Stephen G. Matthews
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Guinea Pigs ◽  
Critical Role ◽  
Methylation Status ◽  
Peripheral Tissues ◽  
Epigenetic Biomarkers ◽  
Differentially Methylated Genes ◽  
Increased Risk ◽  
Synthetic Glucocorticoids

AbstractSynthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.

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