Maternal haemoglobin levels in pregnancy and child DNA methylation : a study in the pregnancy and childhood epigenetics consortium

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels.Peer reviewe

Maternal haemoglobin levels in pregnancy and child DNA methylation: a study in the pregnancy and childhood epigenetics consortium

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels

Influence of Temperature on the Thyroidogenic Effects of Diuron and Its Metabolite 3,4-DCA in Tadpoles of the American Bullfrog (<i>Lithobates catesbeianus</i>)

Temperature is a key variable affecting the timing of amphibian metamorphosis from tadpoles to tetrapods, through the production and subsequent function of thyroid hormones (TH). Thyroid function can be impaired by environmental contaminants as well as temperature. Tadpoles can experience large temperature fluctuations in their habitats and many species are distributed in areas that may be impacted by agriculture. Diuron is a widely used herbicide detected in freshwater ecosystems and may impact endocrine function in aquatic organisms. We evaluated the influence of temperature (28 and 34 °C) on the action of diuron and its metabolite 3,4-dichloroaniline (3,4-DCA) on thyroid function and metamorphosis in tadpoles of <i>Lithobates catesbeianus</i>. Exposure to both compounds induced more pronounced changes in gene expression and plasma 3,3′,5-triiodothyronine (T₃) concentrations in tadpoles treated at higher temperature. T₃ concentrations were increased in tadpoles exposed to 200 ng/L of diuron at 34 °C and an acceleration of metamorphosis was observed for the same group. Transcriptomic responses included alteration of thyroid hormone induced bZip protein (<i>thibz</i>), deiodinases (<i>dio2</i>, <i>dio3</i>), thyroid receptors (<i>trα</i>, <i>trβ</i>) and Krüppel-like factor 9 (<i>klf9</i>), suggesting regulation by temperature on TH-gene expression. These results suggest that environmental temperature should be considered in risk assessments of environmental contaminants for amphibian species

Epigenetic Biomarkers of Lead Exposure and Cardiovascular Disease: Prospective Evidence in the Strong Heart Study

Background: Lead is a cardiotoxic metal with a variety of adverse health effects. In the absence of data on bone lead exposure, epigenetic biomarkers can serve as indicators of cumulative lead exposure and body burden. Herein, we leveraged novel epigenetic biomarkers of lead exposure to investigate their association with cardiovascular disease (CVD) incidence and mortality. Methods and Results: Blood DNA methylation was measured using the Illumina MethylationEPIC BeadChip among 2231 participants of the Strong Heart Study (SHS) at baseline (1989-1991). Epigenetic biomarkers of lead levels in blood, patella, and tibia were estimated using previously identified cytosine-guanine dinucleotide (CpG) sites. CVD incidence and mortality data were available through 2017. Median concentrations of lead epigenetic biomarkers were 13.8 μg/g, 21.3 μg/g, and 2.9 μg/dL in tibia, patella, and blood, respectively. In adjusted models, the hazard ratio (HR) (95% CI) of CVD mortality per doubling increase in lead epigenetic biomarkers were 1.42 (1.07-1.87) for tibia lead, 1.22 (0.93-1.60) for patella lead, and 1.57 (1.16-2.11) for blood lead. The corresponding HRs for incident CVD were 0.99 (0.83-1.19), 1.07 (0.89-1.29), and 1.06 (0.87-1.30). The association between the tibia lead epigenetic biomarker and CVD mortality was modified by sex (interaction P value: 0.014), with men at increased risk (HR, 1.42 [95% CI, 1.17-1.72]) compared with women (HR, 1.04 [95% CI, 0.89-1.22]). Conclusions: Tibia and blood epigenetic biomarkers were associated with increased risk of CVD mortality, potentially reflecting the cardiovascular impact of cumulative and recent lead exposures. These findings support that epigenetic biomarkers of lead exposure may capture some of the disease risk associated with lead exposure.This work was funded by the National Institute of Environmental Health Sciences (T32 ES007322). This work was supported by grants by the National Heart, Lung, and Blood Institute (under contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029, and 75N92019D00030) and previ-ous grants (R01HL090863, R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319) and cooperative agreements (U01HL41642, U01HL41652, U01HL41654, U01HL65520, and U01HL65521), by the National Institute of Environmental Health Sciences (R01ES021367, R01ES025216, P42ES010349, and P30ES009089) and by the Spanish Funds for Research in Health Sciences, Carlos III Health Institute, cofunded by European Regional Development Fund (CP12/03080 and PI15/00071). A. Domingo- Relloso was supported by a fellowship from “la Caixa” Foundation (identifier 100010434) (fellowship code “LCF/BQ/DR19/11740016”). Dr Gao was supported by the Peking University Start-up Grant (BMU2021YJ044). During the preparation of this article, Dr Colicino was supported by R01 ES032242 and P30 ES023515. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Indian Health Service. The funders had no role in study design, data collection and analysis, preparation of the manuscript, or decision to submit the manuscript for publication.S

The Contribution of Declines in Blood Lead Levels to Reductions in Blood Pressure Levels: Longitudinal Evidence in the Strong Heart Family Study

Background Chronic lead exposure is associated with both subclinical and clinical cardiovascular disease. We evaluated whether declines in blood lead were associated with changes in systolic and diastolic blood pressure in adult American Indian participants from the SHFS (Strong Heart Family Study). Methods and Results Lead in whole blood was measured in 285 SHFS participants in 1997 to 1999 and 2006 to 2009. Blood pressure and measures of cardiac geometry and function were obtained in 2001 to 2003 and 2006 to 2009. We used generalized estimating equations to evaluate the association of declines in blood lead with changes in blood pressure; cardiac function and geometry measures were considered secondary. Mean blood lead was 2.04 μg/dL at baseline. After ≈10 years, mean decline in blood lead was 0.67 μg/dL. In fully adjusted models, the mean difference in systolic blood pressure comparing the highest to lowest tertile of decline (>0.91 versus <0.27 μg/dL) in blood lead was −7.08 mm Hg (95% CI, −13.16 to −1.00). A significant nonlinear association between declines in blood lead and declines in systolic blood pressure was detected, with significant linear associations where blood lead decline was 0.1 μg/dL or higher. Declines in blood lead were nonsignificantly associated with declines in diastolic blood pressure and significantly associated with declines in interventricular septum thickness. Conclusions Declines in blood lead levels in American Indian adults, even when small (0.1–1.0 μg/dL), were associated with reductions in systolic blood pressure. These findings suggest the need to further study the cardiovascular impacts of reducing lead exposures and the importance of lead exposure prevention

Additional file 1 of Prenatal exposure to polybrominated diphenyl ethers and BMI Z-scores from 5 to 14 years

Additional file 1: Supplemental Fig. S1. Mean cord PBDE Pearson’s correlations across 10 multiply imputed datasets. The gradient indicates the strength of the correlation. Supplemental Fig. S2. Predicted BMI Z-score growth trajectories from age 5-14 years for children with high (blue, >80th percentile) and low (red) PBDEs. Supplemental Table S1. Summary of follow-up information for the 289 individuals included in the present analysis and the full population of 541 individuals with a BMI measurement between ages 5 and 14. Supplemental Table S2. Sensitivity analyses for associations between cord plasma PBDE measures and overall child BMI Z-scores from age 5–14 years. Supplemental Table S3. Associations between continuous cord plasma PBDE measures and overall child BMI Z-scores from age 5–14 years. Supplemental Table S4. Sensitivity analyses for associations between cord plasma PBDE dichotomized at the 65th and 90th percentiles and overall child BMI Z-scores from age 5–14 years. Supplemental Table S5. Sensitivity analyses for associations between cord plasma PBDEs and trajectories of child BMI from 5 to 14 years. Supplemental Table S6. Sensitivity analyses for associations between cord plasma PBDEs dichotomized at the 65th and 90th percentiles and trajectories of child BMI z-score from 5 to 14 years. Supplemental Table S7. Sensitivity analyses for associations between cord plasma PBDEs and trajectories of child BMI z-score from 5 to 14 years