Persistent DNA methylation changes associated with prenatal mercury exposure and cognitive performance during childhood.
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ABSTRACT:
SUBMITTER: Cardenas A
PROVIDER: S-EPMC5428306 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
Publications
Persistent DNA methylation changes associated with prenatal mercury exposure and cognitive performance during childhood.
Cardenas Andres A Rifas-Shiman Sheryl L SL Agha Golareh G Hivert Marie-France MF Litonjua Augusto A AA DeMeo Dawn L DL Lin Xihong X Amarasiriwardena Chitra J CJ Oken Emily E Gillman Matthew W MW Baccarelli Andrea A AA
Scientific reports 20170321 1
Prenatal exposure to mercury, a known neurotoxic metal, is associated with lower cognitive performance during childhood. Disruption of fetal epigenetic programming could explain mercury's neurodevelopmental effects. We screened for epigenome-wide methylation differences associated with maternal prenatal blood mercury levels in 321 cord blood DNA samples and examined the persistence of these alterations during early (n = 75; 2.9-4.9 years) and mid-childhood (n = 291; 6.7-10.5 years). Among males, ...[more]
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Project description:BackgroundMercury is a global pollutant, and prenatal exposure is associated with adverse health effects. To date, no studies have evaluated the association between prenatal mercury exposure and DNA hydroxymethylation, an epigenetic modification important for tissue differentiation and embryonic development.ObjectivesWe sought to evaluate the association between prenatal mercury exposure and offspring global DNA methylation and hydroxymethylation at birth and test for persistence of the association in childhood.MethodsWithin Project Viva, a U.S. prebirth cohort, we examined associations of maternal second trimester red blood cell mercury (RBC-Hg) concentrations with global 5-hydroxymethylcytosine (%-5hmC) and 5-methylcytosine (%-5mC) DNA content in blood collected at birth (n=306), early childhood (n=68; 2.9 to 4.9 y), and midchildhood (n=260; 6.7 to 10.5 y).ResultsMedian prenatal RBC-Hg concentration was 3.23?g/g [interquartile?range?(IQR)=3.29]. At birth, median cord blood %-5mC, %-5hmC, and their ratio were 4.95%, 0.22%, and 24.37, respectively. The mean adjusted difference [95% confidence interval (CI)] of blood %-5hmC for a doubling in prenatal RBC-Hg concentration was -0.013% (-0.029, 0.002), -0.031% (-0.056, -0.006), and 0.005% (-0.007, 0.018) at birth, early, and midchildhood, respectively. The corresponding relative adjusted change in the genomic ratio of %-5mC to %-5hmC for a doubling in prenatal RBC-Hg concentration was 4.70% (0.04, 9.58), 22.42% (7.73, 39.11), and 0.73% (-4.18, 5.88) at birth, early, and midchildhood, respectively. No associations were present between prenatal maternal RBC-Hg and %-5mC at any time point.ConclusionsPrenatal mercury exposure was associated with lower %-5hmC genomic content and a corresponding increase in the ratio of %-5mC to %-5hmC in cord blood. This association was persistent in early but not midchildhood blood. Our results demonstrate the potential malleability of epigenetic modifications associated with mercury exposure in utero. https://doi.org/10.1289/EHP1467.
| S-EPMC5783674 | biostudies-literature
Project description:Background: How prenatal smoke exposure affects DNA methylation leading to atopic disorders remains to be addressed. Epigenetic biomarkers informative of prenatal smoke exposure and atopic disorders are wanting. Since most children suffering from atopic dermatitis (AD) continue to develop asthma later in life, we explored whether prenatal smoke exposure e induces DNA methylation and searched for predictive epigenetic biomarkers for smoke related atopic disorders. Methods: Methylation differences associated with smoke exposure were screened by Illumina methylation panel for children from the Taiwan birth panel study cohort initially. Information about development of atopic dermatitis (AD) and risk factors were collected. Cord blood cotinine levels were measured to represent prenatal smoke exposure. CpG loci that demonstrated a statistically significant difference in methylation were validated by methylation-dependent fragment separation (MDFS). Differential methylation in three genes (TSLP, GSTT1, and CYB5R3) was identified through the screen and their functions were investigated. Results: Among these, only thymic stromal lymphopoietin (TSLP) gene displayed significant difference in promoter methylation percentage after being validated by MDFS (p=0.029). TSLP gene was further investigated in a larger sample of 92 children from the cohort. Methylation status of the TSLP 5′-CpG island (CGI) was found to be significantly associated with prenatal smoke exposure (OR=3.59, 95%CI=1.49-8.64; cotinine level 0.10 ng/ml, sensitivity= 77%; specificity = 61%) and with AD (OR=4.77, 95%CI=1.47-15.53). The degree of TSLP 5′CGI methylation inversely correlated with TSLP protein expression levels (per unit: β=－6.69 ng/ml; 95% CIs, －12.80~－0.59; p=0.032). Conclusions: The effect of prenatal tobacco smoke exposure on the risk for AD may be mediated through DNA methylation. Cord blood methylated TSLP 5′CGI may be a potential epigenetic biomarker for environmentally-related atopic disorders. The buffy coat and plasma samples were separated and stored at −80°C. DNA (100 ng-500 ng) was extracted from cord white blood cells. Microarrays have been performed to investigate fourteen samples, which were classified as two groups according to cotinine exposure dosage (7 versus 7 : high exposure verses low exposure).
2013-12-31 | E-GEOD-35222 | biostudies-arrayexpress
Project description:BackgroundSmoking while pregnant is associated with a myriad of negative health outcomes in the child. Some of the detrimental effects may be due to epigenetic modifications, although few studies have investigated this hypothesis in detail.ObjectivesTo characterize site-specific epigenetic modifications conferred by prenatal smoking exposure within asthmatic children.MethodsUsing Illumina HumanMethylation27 microarrays, we estimated the degree of methylation at 27,578 distinct DNA sequences located primarily in gene promoters using whole blood DNA samples from the Childhood Asthma Management Program (CAMP) subset of Asthma BRIDGE childhood asthmatics (n?=?527) ages 5-12 with prenatal smoking exposure data available. Using beta-regression, we screened loci for differential methylation related to prenatal smoke exposure, adjusting for gender, age and clinical site, and accounting for multiple comparisons by FDR.ResultsOf 27,578 loci evaluated, 22,131 (80%) passed quality control assessment and were analyzed. Sixty-five children (12%) had a history of prenatal smoke exposure. At an FDR of 0.05, we identified 19 CpG loci significantly associated with prenatal smoke, of which two replicated in two independent populations. Exposure was associated with a 2% increase in mean CpG methylation in FRMD4A (p?=?0.01) and Cllorf52 (p?=?0.001) compared to no exposure. Four additional genes, XPNPEP1, PPEF2, SMPD3 and CRYGN, were nominally associated in at least one replication group.ConclusionsThese data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood. However, the biological significance of these altered loci remains unknown.
| S-EPMC4070909 | biostudies-literature
Project description:BackgroundHuman exposure to the widespread environmental contaminant mercury is a known risk factor for common diseases such as cancer, cardiovascular disease and neurological disorders through poorly characterized mechanisms. Evidence suggests mercury exposure may alter DNA methylation levels, but to date, the effects in early life on a genome-wide scale have not been investigated.MethodsA study sample of 141 newborns was recruited in Baltimore, MD, USA and total mercury and methylmercury were measured in cord blood samples. We quantified genome-wide DNA methylation data using CHARM 2.0, an array-based method, and used region-finding analyses to identify concentration-associated differentially methylated regions (DMRs). To test for replication of these identified DMRs in the pilot, or Vanguard, phase of the National Children's Study (NCS), we compared bisulfite-pyrosequenced DNA at candidate regions from 85 whole cord blood samples with matched first trimester maternal mercury concentration measures.ResultsTotal mercury concentration was associated with methylation at DMRs inside ANGPT2 and near PRPF18 genes [false discovery rate (FDR) < 0.05], as well as DMRs near FOXD2 and within TCEANC2 (FDR< 0.1) genes. Methylmercury concentration was associated with an overlapping DMR within TCEANC2 (FDR< 0.05). In NCS replication analyses, methylation levels at three of four cytosine-guanine DNA dinucleotides (CpG sites) within the TCEANC2 DMR were associated with total mercury concentration (P < 0.05), and this association was diminished after adjusting for estimated cell proportions.ConclusionsEvidence for an association between mercury and DNA methylation at the TCEANC2 region was found, which may represent a mercury-associated shift in cord blood cell composition or a change in methylation within blood cell types. Further confirmatory studies are needed.
| S-EPMC4588863 | biostudies-literature
Project description:BackgroundThere is considerable discussion over the possible harm caused by fetal exposure to mercury, but evidence of such harm is contradictory at levels commonly found in populations with moderate intakes of fish. Further information is needed to inform debate and clarify policy recommendations.MaterialData were collected prospectively for the Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood taken in the first half of pregnancy was assayed for mercury. The outcomes were offspring behavioural assessments collected using the Strengths and Difficulties Questionnaire at seven time points between ages 4 and 16-17 years; five were completed by the mother and two by the teacher. Socioeconomic and biological confounders were first taken into account; further analyses added maternal blood selenium. Separate analyses compared the relationships between prenatal mercury levels and behaviour traits treated as continuous measures in women who ate fish with those who ate no fish in order to determine whether the relationships differed; the hypothesis was that fish consumption had benefits on the brain and masked any mercury effects. In order to prevent Type II errors, the P value for significance was set at 0.10.ResultsPrenatal mercury measurements and offspring behaviour results were available for between 2776 (at 47 months) to 1599 mother-child pairs (at 16-17 years). Even given a P value of 0.10, the number of significant results was no greater than expected apart from the relationships with peer problems at 4, 6 and 10-11 years where the relationships with prenatal mercury were negative (i.e. the greater the level of mercury the fewer the problems the child had with his/her peers). There were no significant differences between the associations with mercury found among the offspring of women who ate fish in pregnancy and those who did not, nor did adjustment for selenium make a difference.ConclusionsThere were no adverse effects of maternal prenatal mercury levels on the behaviour of the offspring. A similar lack of relationship was found when the analyses were confined to those offspring whose mothers had eaten fish in pregnancy, and no consistent differences were found between the fish and non-fish eaters.
| S-EPMC5138154 | biostudies-literature
Project description:Elevated blood pressure in childhood is an important risk factor for hypertension in adulthood. Environmental exposures have been associated with elevated blood pressure over the life course and exposure to mercury (Hg) has been linked to cardiovascular effects in adults. As subclinical vascular changes begin early in life, Hg may play a role in altered blood pressure in children. However, the evidence linking early life Hg exposure to altered blood pressure in childhood has been largely inconsistent. In the ongoing New Hampshire Birth Cohort Study, we investigated prenatal and childhood Hg exposure at multiple time points and associations with blood pressure measurements in 395 young children (mean age 5.5 years, SD 0.4). Hg exposure was measured in children's toenail clippings at age 3 and in urine at age 5-6 years, as well as in maternal toenail samples collected at ∼28 weeks gestation and 6 weeks postpartum, the latter two samples reflecting early prenatal and mid-gestation exposures, respectively. Five measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were averaged for each child using a standardized technique. In covariate-adjusted linear regression analyses, we observed that a 0.1 μg/g increase in child toenail Hg at age 3 or a 0.1 μg/L urine Hg at age 5-6 were individually associated with greater DBP (toenail β: 0.53 mmHg; 95% CI: -0.02, 1.07; urine β: 0.48 mmHg; 95% CI: 0.10, 0.86) and MAP (toenail β: 0.67 mmHg; 95% CI: 0.002, 1.33; urine β: 0.55 mmHg; 95% CI: 0.10, 1.01). Neither early prenatal nor mid-gestation Hg exposure, as measured by maternal toenails, were related to any changes to child BP. Simultaneous inclusion of both child urine Hg and child toenail Hg in models suggested a potentially stronger relationship of urine Hg at age 5-6 with DBP and MAP, as compared to toenail Hg at age 3. Our findings suggest that Hg exposure during childhood is associated with alterations in BP. Childhood may be an important window of opportunity to reduce the impacts of Hg exposure on children's blood pressure, and in turn, long-term health.
| S-EPMC7775884 | biostudies-literature
Project description:Background: How prenatal smoke exposure affects DNA methylation leading to atopic disorders remains to be addressed. Epigenetic biomarkers informative of prenatal smoke exposure and atopic disorders are wanting. Since most children suffering from atopic dermatitis (AD) continue to develop asthma later in life, we explored whether prenatal smoke exposure e induces DNA methylation and searched for predictive epigenetic biomarkers for smoke related atopic disorders. Methods: Methylation differences associated with smoke exposure were screened by Illumina methylation panel for children from the Taiwan birth panel study cohort initially. Information about development of atopic dermatitis (AD) and risk factors were collected. Cord blood cotinine levels were measured to represent prenatal smoke exposure. CpG loci that demonstrated a statistically significant difference in methylation were validated by methylation-dependent fragment separation (MDFS). Differential methylation in three genes (TSLP, GSTT1, and CYB5R3) was identified through the screen and their functions were investigated. Results: Among these, only thymic stromal lymphopoietin (TSLP) gene displayed significant difference in promoter methylation percentage after being validated by MDFS (p=0.029). TSLP gene was further investigated in a larger sample of 92 children from the cohort. Methylation status of the TSLP 5′-CpG island (CGI) was found to be significantly associated with prenatal smoke exposure (OR=3.59, 95%CI=1.49-8.64; cotinine level 0.10 ng/ml, sensitivity= 77%; specificity = 61%) and with AD (OR=4.77, 95%CI=1.47-15.53). The degree of TSLP 5′CGI methylation inversely correlated with TSLP protein expression levels (per unit: β=－6.69 ng/ml; 95% CIs, －12.80~－0.59; p=0.032). Conclusions: The effect of prenatal tobacco smoke exposure on the risk for AD may be mediated through DNA methylation. Cord blood methylated TSLP 5′CGI may be a potential epigenetic biomarker for environmentally-related atopic disorders.
2013-12-31 | GSE35222 | GEO
Project description: Not available
| S-EPMC4211731 | biostudies-literature
Project description:Prenatal exposure to organophosphate pesticides has been shown to negatively affect child neurobehavioral development. Paraoxonase 1 (PON1) is a key enzyme in the metabolism of organophosphates.We examined the relationship between biomarkers of organophosphate exposure, PON1, and cognitive development at ages 12 and 24 months and 6-9 years.The Mount Sinai Children's Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urine samples were collected and analyzed for organophosphate metabolites (n = 360). Prenatal maternal blood was analyzed for PON1 activity and genotype. Children returned for neurodevelopment assessments ages 12 months (n = 200), 24 months (n = 276), and 6-9 (n = 169) years of age.Prenatal total dialkylphosphate metabolite level was associated with a decrement in mental development at 12 months among blacks and Hispanics. These associations appeared to be enhanced among children of mothers who carried the PON1 Q192R QR/RR genotype. In later childhood, increasing prenatal total dialkyl- and dimethylphosphate metabolites were associated with decrements in perceptual reasoning in the maternal PON1 Q192R QQ genotype, which imparts slow catalytic activity for chlorpyrifos oxon, with a monotonic trend consistent with greater decrements with increasing prenatal exposure.Our findings suggest that prenatal exposure to organophosphates is negatively associated with cognitive development, particularly perceptual reasoning, with evidence of effects beginning at 12 months and continuing through early childhood. PON1 may be an important susceptibility factor for these deleterious effects.
| S-EPMC3237356 | biostudies-other
Project description:Trimethyltin (TMT) is an irreversible neurotoxicant. Because prenatal TMT exposure has been reported to induce behavioral changes, this study was conducted to observe gender differences and epigenetic changes using a mouse model. In behavioral testing of offspring at 5 weeks of age, the total times spent in the center, corner, or border zones in the male prenatal TMT-exposed mice were less than those of control unexposed mice in the open-field test. Female TMT-exposed mice scored lower on total numbers of arm entries and percentages of alternations than controls in the Y-maze test with lower body weight. We found that only TMT-exposed males had fewer copies of mtDNA in the hippocampus and prefrontal cortex region than controls. Additional epigenetic changes, including increased 5-methyl cytosine/5-hydroxymethyl cytosine levels in the male TMT hippocampus, were observed. After methylation binding domain (MBD) sequencing, multiple signaling pathways related to metabolism and neurodevelopment, including FoxO signaling, were identified by pathway analysis for differentially methylated regions (DMRs). Increased FOXO3 and decreased ASCL1 expression were also observed in male TMT hippocampi. This study suggests that sex differences and epigenetics should be more carefully considered in prenatal toxicology studies.
| S-EPMC8348768 | biostudies-literature