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Copper associates with differential methylation in placentae from two US birth cohorts.

ABSTRACT: Copper is an essential trace nutrient and an enzymatic cofactor necessary for diverse physiological and biological processes. Copper metabolism is uniquely controlled in the placenta and changes to copper metabolism have been linked with adverse birth outcomes. We investigated associations between patterns of DNA methylation (DNAm; measured at >485 k CpG sites) and copper concentration measured from placentae in two independent mother-infant cohorts: the New Hampshire Birth Cohort Study (NHBCS, n = 306) and the Rhode Island Child Health Study (RICHS, n = 141). We identified nine copper-associated differentially methylated regions (DMRs; adjusted P < 0.05) and 15 suggestive CpGs (raw P < 1e-5). One of the most robust variably methylated CpGs associated with the expression of the antioxidant, GSTP1. Our most robust DMR negatively associates with the expression of the zinc-finger gene, ZNF197 (FDR = 4.5e-11). Genes co-expressed with ZNF197, a transcription factor, are enriched for genes that associate with birth weight in RICHS (OR = 2.9, P = 2.6e-6, N = 194), genes that are near a ZNF197 consensus binding motif (OR = 1.34, P = 0.01, N = 194), and for those classified in GO biological processes growth hormone secretion (P = 3.4e-4), multicellular organism growth (P = 3.8e-4), and molecular functions related to lipid biosynthesis (P = 1.9e-4). Further, putative transcriptional targets for ZNF197 include genes involved in copper metabolism and placentation. Our results suggest that copper metabolism is tied to DNAm in the placenta and that copper-associated patterns in DNAm may mediate normal placentation and foetal development.

SUBMITTER: Kennedy E

PROVIDER: S-EPMC7028322 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background/aimSelenium (Se) levels in pregnancy have been linked to neurobehavioral development of the offspring. DNA methylation is a potential mechanism underlying the impacts of environmental exposures on fetal development; however, very few studies have been done elucidating the role of DNA methylation linking prenatal Se and child neurobehavior. We aimed to investigate the associations between placental Se concentration and epigenome-wide DNA methylation in two U.S. cohorts, and to assess the association between Se-related DNA methylation modifications and newborns' neurobehavior.MethodsWe measured placental Se concentrations in 343 newborns enrolled in the New Hampshire Birth Cohort Study and in 141 newborns in the Rhode Island Child Health Study. Genome-wide placental DNA methylation was measured by HumanMethylation450 BeadChip, and newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales (NNNS). We meta-analyzed the associations between placental Se concentration and DNA methylation in each cohort, adjusting for covariates. We also fit multiple linear regression and ordinal logistic regression for methylation and newborn NNNS summary scores.ResultsWe identified five Se-related differentially methylated CpG sites. Among them was cg09674502 (GFI1), where selenium concentration was positively associated with methylation (β-coefficient = 1.11, FDR-adjusted p-value = 0.045), and where we observed that a one percent methylation level increase was associated with a 15% reduced odds of higher muscle tone in the arms, legs and trunk of newborns, (OR [95% Confidence Interval, CI] = 0.85 [0.77, 0.95]). We also observed for each interquartile range (IQR) increase in selenium concentration in the placenta, there was 1.76 times greater odds of higher hypotonicity (OR [95% CI] = 1.76 [1.12, 2.82]).ConclusionsPlacental selenium concentration was inversely associated with muscle tone of newborns, and hypermethylation of GFI1 could be a potential mechanism underlying this association.

Project description:BackgroundModels that incorporate patterns of multiple cytokine responses to allergens, rather than individual cytokine production, may better predict sensitization and asthma.ObjectiveTo characterize the patterns of peripheral blood mononuclear cells' (PBMCs) cytokine responses to house dust mite (HDM) allergens among children from two population-based birth cohorts using machine learning techniques.MethodsPBMCs collected at 8 years of age from the UK Manchester Asthma and Allergy Study (n = 268) and at 14 years of age from the Australian Raine Study (n = 1374) were cultured with HDM extract (10 ?g/ml). Cytokine expression (IL-13, IL-5, IFN-?, and IL10) was measured in the supernatant. Cytokine patterns were identified using a Gaussian mixture model clustering, and classification stability was assessed by bootstrapping.ResultsA six-class model indicated complex latent structure of cytokine expression. Based on the characteristics of each class, we designated them as follows: 'Nonresponders' (n = 905, 55%); 'IL-10 responders' (n = 49, 3%); 'IFN-? and IL-13 medium responders' (n = 56, 3.4%); 'IL-13 medium responders' (n = 351, 21.4%); 'IL-5 and IL-13 medium responders' (n = 77, 4.7%); and 'IL-13 and IL-5 high responders' (n = 204, 12.4%). 'IL-13 and IL-5 high responders' were at much higher risk of HDM sensitization and asthma compared to all other classes, with 88% of children assigned to this class being sensitized and 28.5% having asthma.ConclusionUsing model-based clustering, we identified several distinct patterns of cytokine response to HDM and observed interplay between cytokine expression level, cytokine patterns (especially IL-13 and IL-5), and clinical outcomes. 'IL-13 and IL-5 high responders' class was strongly associated with HDM sensitization. However, among HDM-sensitized children, one-third showed no PBMC response to HDM, and the majority of HDM-sensitized children did not have asthma or wheeze. Our findings suggest that positive HDM 'allergy tests' and asthma are associated with a broad range of immunophenotypes, which may have important implications for the use of cytokine-targeted treatment approaches.

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Copper associates with differential methylation in placentae from two US birth cohorts.

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