Infant Toenail Research Articles

Prenatal lead (Pb) exposure is associated with differential placental DNA methylation and hydroxymethylation in a human population

ABSTRACT Prenatal lead (Pb) exposure is associated with adverse developmental outcomes and to epigenetic alterations such as DNA methylation and hydroxymethylation in animal models and in newborn blood. Given the importance of the placenta in foetal development, we sought to examine how prenatal Pb exposure was associated with differential placental DNA methylation and hydroxymethylation and to identify affected biological pathways linked to developmental outcomes. Maternal (n = 167) and infant (n = 172) toenail and placenta (n = 115) samples for prenatal Pb exposure were obtained from participants in a US birth cohort, and methylation and hydroxymethylation data were quantified using the Illumina Infinium MethylationEPIC BeadChip. An epigenome-wide association study was applied to identify differential methylation and hydroxymethylation associated with Pb exposure. Biological functions of the Pb-associated genes were determined by overrepresentation analysis through ConsensusPathDB. Prenatal Pb quantified from maternal toenail, infant toenail, and placenta was associated with 480, 27, and 2 differentially methylated sites (q < 0.05), respectively, with both increases and decreases associated with exposure. Alternatively, we identified 2, 1, and 14 differentially hydroxymethylated site(s) associated with maternal toenail, infant toenail, and placental Pb, respectively, with most showing increases in hydroxymethylation with exposure. Significantly overrepresented pathways amongst genes associated with differential methylation and hydroxymethylation (q < 0.10) included mechanisms pertaining to nervous system and organ development, calcium transport and regulation, and signalling activities. Our results suggest that both methylation and hydroxymethylation in the placenta can be variable based on Pb exposure and that the pathways impacted could affect placental function.

Periconceptional and prenatal exposure to metal mixtures in relation to behavioral development at 3 years of age.

Behavioral effects of prenatal exposure to mixtures of essential and toxic metals are incompletely understood. We investigated neurodevelopmental effects of prenatal metal exposures in the New Hampshire Birth Cohort Study, a prospective birth cohort. We measured metals (As, Cu, Mn, Pb, Se, Zn) in maternal prenatal and postnatal toenails and infant toenails, reflecting exposures during periconception and early pregnancy, mid pregnancy, and late pregnancy and early neonatal life, respectively. Mothers completed the Social Responsiveness Scale, 2nd ed. (SRS-2) and the Behavior Assessment System for Children, 2nd ed. (BASC-2) to assess their child's neurobehavior at 3 years. We used mean field variational Bayes for lagged kernel machine regression to investigate associations of toenail metal concentrations with SRS-2 Total Scores and BASC-2 composite scores (SRS-2: n = 371; BASC-2: n = 318). Infant toenail Mn was associated with poorer performance on multiple BASC-2 composite scores. Maternal postnatal toenail As was associated with worse scores on the BASC-2 Internalizing Problems and Behavioral Symptoms Index. Associations with Mn were generally stronger in males, and associations with As were generally stronger in females. Other metals, including Pb, were weakly or inconsistently associated with BASC-2 outcomes, and there were no strong associations of individual metals and SRS-2 Total Scores. We observed suggestive evidence of interaction between As and Se for SRS-2 Total Scores and BASC-2 Adaptive Skills, though overall evidence of interactions between metals was weak. Our results support the hypothesis that exposure to Mn and As in mid to late pregnancy may be neurodevelopmentally harmful.

Nutrient-toxic element mixtures and the early postnatal gut microbiome in a United States longitudinal birth cohort

BackgroundThe infant microbiome contributes to health status across the lifespan, but environmental factors affecting microbial communities are poorly understood, particularly when toxic and essential elements interact. ObjectiveWe aimed to identify the associations between a spectrum of other early-postnatal nutrient or toxic elemental exposures measured and the infant gut microbiome. MethodsOur analysis included 179 six-week-old infants from the New Hampshire Birth Cohort Study. Eleven elements were measured in infant toenail clippings. The gut microbiome was assessed using 16S rRNA V4-V5 hypervariable region targeted sequencing. Multivariable zero-inflated logistic normal regression (MZILN) was used to model the association between element concentrations and taxon relative abundance. To explore interactive and nonlinear associations between the exposures and specific taxa we employed Bayesian Kernel Machine Regression (BKMR). Effect modification by delivery mode, feeding mode, peripartum antibiotic exposure, and infant sex was assessed with stratified models. ResultsWe found a negative association between arsenic and microbial diversity in the full population that was accentuated among infants exposed to peripartum antibiotics. Arsenic, cadmium, copper, iron, lead, manganese, nickel, selenium, tin, and zinc were each associated with differences in at least one taxon in the full study population, with most of the related taxa belonging to the Bacteroides and Lactobacillales. In stratified analyses, mercury, in addition to the other elements, was associated with specific taxa. Bifidobacterium, which associated negatively with zinc in MZILN and BKMR models, had a quadratic association with arsenic concentrations. These associations varied with the concentration of the other element. ConclusionsEarly postnatal toxic and nutrient elemental exposures are associated with differences in the infant microbiome. Further research is needed to clarify the whether these alterations are a biomarker of exposure or if they have implications for child and lifelong health.

Infant toenail metal concentrations associated with gut microbial diversity and specific taxa abundance

Infant toenail metal concentrations associated with gut microbial diversity and specific taxa abundance

Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

ABSTRACTEpigenetic alterations related to prenatal neurotoxic metals exposure may be key in understanding the origins of cognitive and neurobehavioral problems in children. Placental glucocorticoid receptor (NR3C1) methylation has been linked to neurobehavioral risk in early life, but has not been examined in response to neurotoxic metals exposure despite parallel lines of research showing metals exposure and NR3C1 methylation each contribute to a similar set of neurobehavioral phenotypes. Thus, we conducted a study of prenatal neurotoxic metals exposure and placental NR3C1 methylation in a cohort of healthy term singleton pregnancies from Rhode Island, USA (n = 222). Concentrations of arsenic (As; median 0.02 ug/g), cadmium (Cd; median 0.03 μg/g), lead (Pb; median 0.40 μg/g), manganese (Mn; median 0.56 μg/g), mercury (Hg; median 0.02 μg/g), and zinc (Zn; 145.18 μg/g) measured in infant toenails were categorized as tertiles. Multivariable linear regression models tested the independent associations for each metal with NR3C1 methylation, as well as the cumulative risk of exposure to multiple metals simultaneously. Compared to the lowest exposure tertiles, higher levels of As, Cd, Pb, Mn, and Hg were each associated with increased placental NR3C1 methylation (all P<0.02). Coefficients for these associations corresponded with a 0.71–1.41 percent increase in NR3C1 methylation per tertile increase in metals concentrations. For Zn, the lowest exposure tertile compared with the highest tertile was associated with 1.26 percent increase in NR3C1 methylation (P=0.01). Higher cumulative metal risk scores were marginally associated with greater NR3C1 methylation. Taken together, these results indicate that prenatal exposure to neurotoxic metals may affect the offspring's NR3C1 activity, which may help explain cognitive and neurodevelopmental risk later in life.

Assessment of human dietary exposure to arsenic through rice

Rice accumulates 10-fold higher inorganic arsenic (i-As), an established human carcinogen, than other grains. This review summarizes epidemiologic studies that examined the association between rice consumption and biomarkers of arsenic exposure. After reviewing the literature we identified 20 studies, among them included 18 observational and 2 human experimental studies that reported on associations between rice consumption and an arsenic biomarker. Among individuals not exposed to contaminated water, rice is a source of i-As exposure – rice consumption has been consistently related to arsenic biomarkers, and the relationship has been clearly demonstrated in experimental studies. Early-life i-As exposure is of particular concern due to its association with lifelong adverse health outcomes. Maternal rice consumption during pregnancy also has been associated with infant toenail total arsenic concentrations indicating that dietary exposure during pregnancy results in fetal exposure. Thus, the collective evidence indicates that rice is an independent source of arsenic exposure in populations around the world and highlights the importance of investigating its affect on health.

Placental Metal Concentrations in Relation to Maternal and Infant Toenails in a U.S. Cohort.

Metal contaminants cross the placenta, presenting a heightened risk of perturbing fetal development. Information about placental concentrations and transfer of multiple potentially toxic metals from low to moderate exposure is lacking. We measured concentrations of Cd, Pb, Hg, Mn, Se, and Zn in 750 placentas collected from women enrolled in the New Hampshire Birth Cohort Study and examined the correlation between elements, and profiles of potentially toxic metals (Cd, Pb, Hg, and Mn) stratified by nutrient concentrations (Zn and Se) using principal components analyses. We further examined the indirect effects of maternal metal concentrations on infant metal concentrations through placental metal concentrations using structural equation models. Placental metal concentrations were all correlated, particularly Zn and Mn, and Zn and Cd, and the principal component of metals differed by stratum of high versus low Zn and Se. Associations were observed between placenta and maternal toenail Se (β = 63.49; P < 0.0001) and Pb (β = 0.90; P < 0.0001) but not other metals. Structural equation models did not indicate any statistically significant indirect effects through placental metal concentrations. Placental metal concentrations may represent a distinct biomarker of metal exposure and adverse health impacts to the fetus, particularly those stemming from the placenta.

Maternal-infant biomarkers of prenatal exposure to arsenic and manganese.

Because arsenic (As) and manganese (Mn) are able to pass the placenta, infants among exposed populations may be exposed to considerable levels in utero. The main objective of this paper is to evaluate infant toenails, hair, and cord blood as biomarkers of prenatal exposure to As and Mn and determine the relationship between maternal and infant As and Mn concentrations in these biomarkers. Of the 1196 pregnant women in Bangladesh who were monitored throughout pregnancy until 1 month post-partum and completed all study visits, we included 711 mother-infant pairs who had at least one maternal and one infant biomarker of exposure available for analysis. Toenail and hair samples were collected from the women during the first trimester and 1 month post-partum and from the infants at the age of 1 month. Cord blood was collected at the time of delivery. Maternal toenail concentrations were correlated with infant toenail concentrations for As and Mn (n=258, r=0.52, 95% CI: 0.43-0.60, P<0.0001 and r=0.39, 95% CI: 0.28-0.49, P<0.0001), respectively. Similarly, maternal hair concentrations were correlated with infant hair As (n=685, r=0.61, 95% CI: 0.56-0.65, P<0.0001) and infant hair Mn (n=686, r=0.21, 95% CI: 0.14-0.28, P<0.0001). Cord blood As was correlated with infant toenail and hair As, although cord blood Mn was only correlated with infant toenail. Toenails and cord blood appear to be valid biomarkers of maternal-fetal transfer of As and Mn, whereas hair may not be a suitable biomarker for in utero exposure to Mn.

Placental arsenic concentrations in relation to both maternal and infant biomarkers of exposure in a US cohort.

Arsenic crosses the placenta and may have adverse consequences in utero and later in life. At present, little is known about arsenic concentrations in placenta and their relation to maternal and infant exposures particularly at common levels of exposure. We measured placenta arsenic in a US cohort potentially exposed via drinking water from private wells, and evaluated the relationships between placenta and maternal and infant biomarker arsenic concentrations. We measured total arsenic concentrations in placental samples from women enrolled in the New Hampshire Birth Cohort Study (N=766). We compared these data to maternal urinary arsenic (total arsenic and individual species) collected at approximately 24-28 week gestation, along with maternal post-partum toenails and infant toenails using non-parametric multivariate analysis of log10-transformed data. We also examined the association between placental arsenic and household drinking water arsenic. Placenta arsenic concentrations were related to arsenic concentrations in maternal urine (β 0.55, P value <0.0001), maternal (β 0.30, P value 0.0196) and infant toenails (β 0.40, P value 0.0293) and household drinking water (β 0.09, P value <0.0001). Thus, our data suggest that placenta arsenic concentrations reflect both maternal and infant exposures.

Placental DNA Methylation Related to Both Infant Toenail Mercury and Adverse Neurobehavioral Outcomes.

BackgroundPrenatal mercury (Hg) exposure is associated with adverse child neurobehavioral outcomes. Because Hg can interfere with placental functioning and cross the placenta to target the fetal brain, prenatal Hg exposure can inhibit fetal growth and development directly and indirectly.ObjectivesWe examined potential associations between prenatal Hg exposure assessed through infant toenail Hg, placental DNA methylation changes, and newborn neurobehavioral outcomes.MethodsThe methylation status of > 485,000 CpG loci was interrogated in 192 placental samples using Illumina’s Infinium HumanMethylation450 BeadArray. Hg concentrations were analyzed in toenail clippings from a subset of 41 infants; neurobehavior was assessed using the NICU Network Neurobehavioral Scales (NNNS) in an independent subset of 151 infants.ResultsWe identified 339 loci with an average methylation difference > 0.125 between any two toenail Hg tertiles. Variation among these loci was subsequently found to be associated with a high-risk neurodevelopmental profile (omnibus p-value = 0.007) characterized by the NNNS. Ten loci had p < 0.01 for the association between methylation and the high-risk NNNS profile. Six of 10 loci reside in the EMID2 gene and were hypomethylated in the 16 high-risk profile infants’ placentas. Methylation at these loci was moderately correlated (correlation coefficients range, –0.33 to –0.45) with EMID2 expression.ConclusionsEMID2 hypomethylation may represent a novel mechanism linking in utero Hg exposure and adverse infant neurobehavioral outcomes.CitationMaccani JZ, Koestler DC, Lester B, Houseman EA, Armstrong DA, Kelsey KT, Marsit CJ. 2015. Placental DNA methylation related to both infant toenail mercury and adverse neurobehavioral outcomes. Environ Health Perspect 123:723–729; http://dx.doi.org/10.1289/ehp.1408561

Placental DNA Methylation Related to Both Infant Toenail Mercury and Adverse Neurobehavioral Outcomes

Prenatal exposure to mercury (Hg) is associated with adverse neurobehavioral outcomes in children. As Hg can interfere with normal placental functioning, as well as cross the placenta and target th...

Infant toenails as a biomarker of in utero arsenic exposure.

A growing body of evidence suggests that in utero and early-life exposure to arsenic may have detrimental effects on children, even at the low to moderate levels common in the United States and elsewhere. In a sample of 170 mother-infant pairs from New Hampshire, we determined infant exposure to in utero arsenic by evaluating infant toenails as a biomarker using inductively coupled plasma mass spectrometry. Infant toenail arsenic concentration correlated with maternal postpartum toenail concentrations (Spearman's correlation coefficient 0.34). In adjusted linear models, a doubling of maternal toenail arsenic concentration was associated with a 53.8% increase in infant toenail arsenic concentration as compared with 20.4% for a doubling of maternal urine arsenic concentration. In a structural equation model, a doubling of the latent variable integrating maternal toenail and urine arsenic concentrations was associated with a 67.5% increase in infant toenail arsenic concentration. A similar correlation between infant and maternal postpartum toenail concentrations was observed in a validation cohort of 130 mother-infant pairs from Rhode Island. In utero exposure to arsenic occurs through maternal water and dietary sources, and infant toenails appear to be a reliable biomarker for estimating arsenic exposure during the critical window of gestation.