Maternal Blood Cadmium Concentrations and Whole Blood DNA Methylation during Pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI)

2018 ◽  
Vol 2018 (1) ◽  
Author(s):  
Tun (Max) M Aung ◽  
Kelly Bakulski ◽  
Jason Feinberg ◽  
John Dou ◽  
John Meeker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Maternal Blood ◽  
Longitudinal Investigation ◽  
Blood Cadmium

scholarly journals Maternal blood metal concentrations and whole blood DNA methylation during pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI)

2020 ◽  
Author(s):  
Max T. Aung ◽  
Kelly M. Bakulski ◽  
Jason I. Feinberg ◽  
John F. Dou ◽  
John D. Meeker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Linear Regression ◽  
Whole Blood ◽  
Maternal Blood ◽  
Nervous System Development ◽  
Q Value ◽  
450K Array ◽  
Smoking During Pregnancy ◽  
Longitudinal Investigation ◽  
Cadmium Lead

AbstractBackgroundMetals exposures have important health effects in pregnancy. The maternal epigenome may be responsive to these exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation.MethodsIn the Early Autism Risk Longitudinal Investigation (EARLI) cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) in 215 participants using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured in the same specimens on the Illumina 450K array (201 participants). A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal to elucidate downstream pathways.ResultsIn multiple linear regression, we observed hypermethylation at 11 DNA methylation sites associated with lead (FDR q-value <0.1), near the genes CYP24A1, ASCL2, FAT1, SNX31, NKX6-2, LRC4C, BMP7, HOXC11, PCDH7, ZSCAN18, and VIPR2. Lead associated sites were enriched (FDR q-value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR q-value <0.1), one of which was near the gene ARID2. Manganese associated sites were enriched for cellular metabolism pathways (FDR q-value<0.1). Effect estimates for DNA methylation sites associated (p<0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ >0.86).DiscussionSingle DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways. Future studies should replicate our findings to characterize potential toxicological mechanisms of trace metals through the maternal epigenome.

scholarly journals Maternal blood metal concentrations and whole blood DNA methylation during pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI)

Epigenetics ◽  
2021 ◽  
pp. 1-16
Author(s):  
Max T. Aung ◽  
Kelly M. Bakulski ◽  
Jason I. Feinberg ◽  
John F. Dou ◽  
John D. Meeker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Maternal Blood ◽  
Metal Concentrations ◽  
Longitudinal Investigation

scholarly journals Autism-Associated DNA Methylation at Birth From Multiple Tissues Is Enriched for Autism Genes in the Early Autism Risk Longitudinal Investigation

2021 ◽  
Vol 14 ◽  
Author(s):  
Kelly M. Bakulski ◽  
John F. Dou ◽  
Jason I. Feinberg ◽  
Max T. Aung ◽  
Christine Ladd-Acosta ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Late Pregnancy ◽  
Maternal Blood ◽  
Autism Spectrum ◽  
Epigenetic Mark ◽  
Global Methylation ◽  
Risk Genes ◽  
Longitudinal Investigation ◽  
Research Initiative

Background: Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Few ASD studies have considered prospective designs with DNA methylation measured in multiple tissues and tested overlap with ASD genetic risk loci.Objectives: To estimate associations between DNA methylation in maternal blood, cord blood, and placenta and later diagnosis of ASD, and to evaluate enrichment of ASD-associated DNA methylation for known ASD-associated genes.Methods: In the Early Autism Risk Longitudinal Investigation (EARLI), an ASD-enriched risk birth cohort, genome-scale maternal blood (early n = 140 and late n = 75 pregnancy), infant cord blood (n = 133), and placenta (maternal n = 106 and fetal n = 107 compartments) DNA methylation was assessed on the Illumina 450k HumanMethylation array and compared to ASD diagnosis at 36 months of age. Differences in site-specific and global methylation were tested with ASD, as well as enrichment of single site associations for ASD risk genes (n = 881) from the Simons Foundation Autism Research Initiative (SFARI) database.Results: No individual DNA methylation site was associated with ASD at genome-wide significance, however, individual DNA methylation sites nominally associated with ASD (P &lt; 0.05) in each tissue were highly enriched for SFARI genes (cord blood P = 7.9 × 10–29, maternal blood early pregnancy P = 6.1 × 10–27, maternal blood late pregnancy P = 2.8 × 10–16, maternal placenta P = 5.6 × 10–15, fetal placenta P = 1.3 × 10–20). DNA methylation sites nominally associated with ASD across all five tissues overlapped at 144 (29.5%) SFARI genes.Conclusion: DNA methylation sites nominally associated with later ASD diagnosis in multiple tissues were enriched for ASD risk genes. Our multi-tissue study demonstrates the utility of examining DNA methylation prior to ASD diagnosis.

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.

scholarly journals Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chen Yao ◽  
Roby Joehanes ◽  
Rory Wilson ◽  
Toshiko Tanaka ◽  
Luigi Ferrucci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Dna Methylation ◽  
Cigarette Smoking ◽  
Association Study ◽  
Whole Blood ◽  
Lung Diseases ◽  
Epigenetic Modification ◽  
Blood Gene Expression ◽  
Increased Risk

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

scholarly journals Urate-induced epigenetic modifications in myeloid cells

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
M. Badii ◽  
O. I. Gaal ◽  
M. C. Cleophas ◽  
V. Klück ◽  
R. Davar ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Myeloid Cells ◽  
Cytokine Signaling ◽  
Human Monocytes ◽  
Methylation Array ◽  
Histone 3 ◽  
Msu Crystals

Abstract Objectives Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1β. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. Methods Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. Results High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. Conclusion Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.

scholarly journals DNA Methylation in Whole Blood: Uses and Challenges

2015 ◽  
Vol 2 (2) ◽  
pp. 145-154 ◽  
Author(s):  
E. Andres Houseman ◽  
Stephanie Kim ◽  
Karl T. Kelsey ◽  
John K. Wiencke
Keyword(s):  
Dna Methylation ◽  
Whole Blood

scholarly journals Butyrate and related epigenetic changes link Parkinson's disease to inflammatory bowel disease and depressive symptoms

2021 ◽  
Author(s):  
Aoji Xie ◽  
Elizabeth Ensink ◽  
Peipei Li ◽  
Juozas Gordevicius ◽  
Lee L. Marshall ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Depressive Symptoms ◽  
Gut Microbiome ◽  
Whole Blood ◽  
Blood Samples ◽  
Targeted Bisulfite Sequencing ◽  
Genome Wide ◽  
Whole Blood Samples

Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced Roseburia, Romboutsia, and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases.

Sign in / Sign up

Export Citation Format

Share Document