Comparisons between animal and human neurotoxicology studies are a foundation of risk assessment, but are hindered by differences in measured behaviors. The Radial Arm Maze (RAM), a rodent visuospatial learning and memory task, has a computerized version for use in children, which may help improve comparisons between animal and human studies.
To describe the characteristics and correlates of the Virtual Radial Arm Maze (VRAM) in 255 children age 10–15 years from Italy.
We administered the VRAM using a laptop computer and measured children’s performance using the latency, distance, and working/reference memory errors during eight trials. Using generalized linear mixed models, we described VRAM performance in relation to demographic factors, child activities, and several standard neuropsychologic tests (Italian translations), including the Conners Parent Rating Scales-Short Version (CPRS), California Verbal Learning Test (CVLT), Wechsler Intelligence Scales for Children, finger tapping speed, reaction time, and motor skills.
Children’s VRAM performance tended to improve between trials 1–6 and then plateaued between trials 6–8. Males finished the task 14 seconds faster (95% Confidence Interval [CI]:-20, -9) than females. Children who played 2+ hours of video games per day finished 16 seconds faster (CI:-26, -6) and with 34% (CI:5, 54%) fewer working memory errors than children who reported not playing video games. Higher IQ and better CVLT scores were associated with better VRAM performance. Higher Cognitive/Inattention CPRS scores were associated with more working (11%; CI:1, 22) and reference memory errors (7%; CI:1, 12).
Consistent with animal studies, VRAM performance improved over the course of test trials and males performed better than females. Better VRAM performance was related to higher IQ, fewer inattentive behaviors, and better verbal memory. The VRAM may help improve the integration and comparison between animal and epidemiological studies of environmental neurotoxicants.
Child behavior; computerized tests; environmental chemicals; epidemiology; toxicology
The identification of susceptible periods to Pb-induced decrements in childhood cognitive abilities remains elusive.
To draw inferences about windows of susceptibility using the pattern of associations between serial childhood blood lead (BPb) concentrations and children’s cognitive abilities at 4 years of age among 1035 mother–child pairs enrolled in 4 prospective birth cohorts from Mexico City.
Multiple longitudinally collected BPb measurements were obtained from children (1, 2, 3, and 4 years) between 1994 and 2007. Child cognitive abilities were assessed at 4 years using the general cognitive index (GCI) of the McCarthy Scales of Children’s Abilities. We used multivariable linear regression to estimate the change in cognitive abilities at 4 years of age with a 10 μg/dL increase in childhood BPb concentrations adjusting for maternal IQ, education, marital status, child sex, breastfeeding duration, and cohort.
In separate models for each BPb measurement, 2 year BPb concentrations were most strongly associated with reduced GCI scores at 4 years after adjusting for confounders (β: −3.8; 95% confidence interval CI: −6.3, −1.4). Mutual adjustment for other BPb concentrations in a single model resulted in larger, but less precise estimate between 2 year BPb concentrations and GCI scores at 4 years of age (β: −7.1; 95% CI: −12, −2.0). The association between 2 year BPb and GCI was not heterogeneous (p = 0.89), but some BPb and GCI associations varied in magnitude and direction across the cohorts. Additional adjustment for child hemoglobin, birth weight, gestational age, gestational BPb concentrations, or test examiner did not change the pattern of associations.
Higher BPb concentrations at 2 years of age were most predictive of decreased cognitive abilities among these Mexico City children; however, the observed pattern may be due to exposure, outcome, or cohort related factors. These results may help developing countries more efficiently implement childhood Pb prevention strategies.
Lead; Children; Epidemiology; Cognitive abilities; Windows of development
Studies show that exposure to air pollution damages human health, but the mechanisms are not fully understood. One suggested pathway is via oxidative stress.
This study is to examine associations between exposure to air pollution and oxidative DNA damage, as indicated by urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG) concentrations in aging participants during 2006-2008.
We fit linear regression models to examine associations between air pollutants and 8-OHdG adjusting for potential confounders.
8-OHdG was significantly associated with ambient particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5), the number of particles (PN), nitrogen dioxide (NO2), maximal 1-hour ozone (O3), sulfate (SO42-) and organic carbon (OC), but not with black carbon (BC), carbon monoxide (CO) or elemental carbon (EC). Effects were more apparent with multi-week averages of exposures. Per IQR increases of 21-day averages of PM2.5, PN, BC, EC, OC, CO, SO42-, NO2 and maximal 1-hour O3 were associated with 30.8% (95% confidence interval (CI): 9.3%, 52.2%), -13.1% (95%CI: -41.7%, 15.5%), 3.0% (95% CI: -19.8%, 25.8%), 5.3% (95% CI: -23.6%, 34.2%), 24.4% (95% CI: 1.8%, 47.1%), -2.0% (95% CI: -12.4%, 8.3%), 29.8% (95% CI: 6.3%, 53.3%), 32.2% (95% CI: 7.4%, 56.9%) and 47.7% (95% CI: 3.6%, 91.7%) changes in 8-OHdG, respectively.
This study suggests that aging participants experienced an increased risk of developing oxidative DNA injury after exposure to the secondary, but not primary ambient pollutants.
8-Hydroxy-2′-Deoxyguanosine; air pollution; DNA damage; oxidative stress; biomarker
Arsenic exposure has been linked to epigenetic modifications such as DNA methylation in in vitro and animal studies. This association has also been explored in highly exposed human populations, but studies among populations environmentally exposed to low arsenic levels are lacking.
We evaluated the association between exposure to arsenic, measured in toenails, and blood DNA methylation in Alu and Long Interspersed Nucleotide Element-1 (LINE-1) repetitive elements in elderly men environmentally exposed to low levels of arsenic. We also explored potential effect modification by plasma folate, cobalamin (vitamin B12), and pyridoxine (vitamin B6). The study population was 581 participants from the Normative Aging Study in Boston, of whom 434, 140, and 7 had 1, 2, and 3 visits, respectively, between 1999-2002 and 2006-2007. We used mixed-effects models and included interaction terms to assess potential effect modification by nutritional factors.
There was a trend of increasing Alu and decreasing LINE-1 DNA methylation as arsenic exposure increased. In subjects with plasma folate below the median (< 14.1 ng/ml), arsenic was positively associated with Alu DNA methylation (β=0.08 [95% confidence interval = 0.03 to 0.13] for one interquartile range [0.06μg/g] increase in arsenic) while a negative association was observed in subjects with plasma folate above the median (β=-0.08 [-0.17 to 0.01]).
We found an association between arsenic exposure and DNA methylation in Alu repetitive elements that varied by folate level. This suggests a potential role for nutritional factors in arsenic toxicity.
Endocrine disrupting chemicals that are structurally similar to steroid or amine hormones have the potential to mimic endocrine endpoints at the receptor level. However, more recently, epigenetic-induced alteration in gene expression has emerged as an alternative way in which environmental compounds may exert endocrine effects. We review concepts related to environmental epigenetics and relevance for endocrinology through three broad examples, 1) effect of early-life nutritional exposures on future obesity and insulin resistance, 2) effect of lifetime environmental exposures such as ionizing radiation on endocrine cancer risk, and 3) potential for compounds previously classified as endocrine disrupting to additionally or alternatively exert effects through epigenetic mechanisms. The field of environmental epigenetics is still nascent, and additional studies are needed to confirm and reinforce data derived from animal models and preliminary human studies. Current evidence suggests that environmental exposures may significantly impact expression of endocrine-related genes and thereby affect clinical endocrine outcomes.
Epigenetics; DNA methylation; histone modifications; toxicology; endocrine disrupters
Purpose of review
Despite advances in medical care, preterm birth and its associated racial/ethnic disparities remain major public health issues. Environmental exposures may contribute to racial disparities in preterm birth.
Recent work in Iran demonstrated lead levels <10 μg/dl to be associated with preterm birth and premature rupture of membranes. Data on air pollution are mixed. A study in California found exposure to nitric oxide species to be associated with preterm birth. However, results from large birth cohorts in the Netherlands found no association. Interestingly, a study in South Korea recently demonstrated that socioeconomic status modifies the association between air pollution and preterm birth. A recent promising study randomized minority pregnant women in Washington DC to cognitive behavioral therapy vs. usual care to decrease exposure to environmental tobacco smoke (ETS). The investigators reported reductions in ETS exposure and the risk of very preterm birth.
Clues about potential mechanisms underlying disparities in preterm birth can be gained from exploring differences in environmental exposures. Investigators should include environmental variables when studying birth outcomes. Such efforts should result in targeted interventions to decrease the incidence of preterm birth and its disparities.
preterm; disparities; environment; lead; air pollution
Exposure to organophosphate (OP) pesticides is common, and although these compounds have known neurotoxic properties, few studies examined risks for children in the general population.
To examine the association between the concentrations of urinary dialkyl phosphate (DAP) metabolites of OPs and attention deficit/hyperactivity disorder (ADHD) in children age 8 to 15 years.
Participants and Methods
Cross-sectional data from the National Health and Nutrition Examination Survey (2000–2004) were available for 1,139 children representative of the general U.S. population. A structured interview with a parent was used to ascertain ADHD diagnostic status, based on slightly modified criteria of the Diagnostic and Statistical Manual of Mental Disorders-IV.
One hundred nineteen children met the diagnostic criteria for ADHD. Children with higher concentrations of urinary DAPs, especially dimethyl alkylphosphates (DMAP), were more likely to be diagnosed with ADHD. A 10-fold increase in DMAP concentration was associated with an odds ratio (OR) of 1.55 (95% confidence intervals [CI], 1.14–2.10), after adjusting for sex, age, race/ethnicity, poverty-income ratio, fasting duration, and urinary creatinine concentration. For the most commonly detected DMAP metabolite, dimethylthiophosphate, children with levels higher than the median of detectable concentrations had double the odds of ADHD (adjusted OR, 1.93 [95% CI, 1.23–3.02]) compared with those with non-detectable levels.
These findings support the hypothesis that OP exposure, at levels common in U.S. children, may contribute to ADHD prevalence. Prospective studies are needed to establish whether this association is causal.
attention deficit/hyperactivity disorder; ADHD; pesticides; organophosphates; OP; National Health and Nutrition Examination Survey; NHANES; Center for Health Statistics; NCHS; Centers for Disease Control and Prevention; CDC
Background: Ambient air pollution may have neurotoxic effects in children. Data examining associations between traffic-related air pollution and attention domains remain sparse.
Objectives: We examined associations between black carbon (BC), a marker of traffic particles, and attention measures ascertained at 7–14 years of age among 174 children in a birth cohort based in the Boston, Massachusetts, area.
Methods: We estimated BC levels using a validated spatial–temporal land-use regression model based on residence during children’s lifetime. Children completed the Conner’s Continuous Performance Test (CPT) measuring omission errors, commission errors, and hit reaction time (HRT), with higher scores indicating increased errors or slower reaction time. Multivariable-adjusted linear regression analyses were used to examine associations between BC and each attention outcome.
Results: Children were primarily Hispanic (56%) and Caucasian (41%); 53% were boys. We found a positive association between higher BC levels with increased commission errors and slower HRT, adjusting for child IQ, age, sex, blood lead level, maternal education, pre- and postnatal tobacco smoke exposure, and community-level social stress. Notably, the association was weaker, though still positive, for the highest BC quartile relative to the middle two quartiles. Sex-stratified analysis demonstrated statistically significant associations between BC and both commission errors and HRT in boys, but BC was not significantly associated with any of the CPT outcomes in girls.
Conclusions: In this population of urban children, we found associations between BC exposure and higher commission errors and slower reaction time. These associations were overall more apparent in boys than girls.
attention; children; Conners’ Continuous Performance Test; hit reaction time; traffic-related air pollution; urban
Dysregulation of synaptic development and function has been implicated in the pathophysiology of neurodegenerative disorders and mental disease. A neurotrophin that has an important function in neuronal and synaptic development is brain-derived neurotrophic factor (BDNF). In this communication, we examined the effects of lead (Pb2+) exposure on BDNF-tropomyosin-related kinase B (TrkB) signaling during the period of synaptogenesis in cultured neurons derived from embryonic rat hippocampi. We show that Pb2+ exposure decreases BDNF gene and protein expression, and it may also alter the transport of BDNF vesicles to sites of release by altering Huntingtin phosphorylation and protein levels. Combined, these effects of Pb2+ resulted in decreased concentrations of extracellular mature BDNF. The effect of Pb2+ on BDNF gene expression was associated with a specific decrease in calcium-sensitive exon IV transcript levels and reduced phosphorylation and protein expression of the transcriptional repressor methyl-CpG–binding protein (MeCP2). TrkB protein levels and autophosphorylation at tyrosine 816 were significantly decreased by Pb2+ exposure with a concomitant increase in p75 neurotrophin receptor (p75NTR) levels and altered TrkB-p75NTR colocalization. Finally, phosphorylation of Synapsin I, a presynaptic target of BDNF-TrkB signaling, was significantly decreased by Pb2+ exposure with no effect on total Synapsin I protein levels. This effect of Pb2+ exposure on Synapsin I phosphorylation may help explain the impairment in vesicular release documented by us previously (Neal, A. P., Stansfield, K. H., Worley, P. F., Thompson, R. E., and Guilarte, T. R. (2010). Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of N-Methyl-D-aspartate receptor (NMDAR) dependent BDNF signaling. Toxicol. Sci. 116, 249–263) because it controls vesicle movement from the reserve pool to the readily releasable pool. In summary, the present study demonstrates that Pb2+ exposure during the period of synaptogenesis of hippocampal neurons in culture disrupts multiple synaptic processes regulated by BDNF-TrkB signaling with long-term consequences for synaptic function and neuronal development.
BDNF; TrkB; p75NTR; MeCP2; epigenetics; Huntingtin; Synapsin I; phosphorylation; Pb2+; hippocampus; neuron; synaptogenesis
Previous studies found effect modification of associations between traffic-related air pollution and cardiovascular outcomes by polymorphisms in the hemochromatosis gene (HFE). As traffic-related air pollution may impact cognition through effects on cardiovascular health or through mechanisms which may also influence cardiovascular outcomes, we hypothesized that HFE polymorphisms would also modify a previously observed association between traffic-related air pollution exposure and cognition in older men.
We considered data from 628 participants of the VA Normative Aging Study. We estimated long term exposure to black carbon (BC), a marker of traffic related air pollution, using a spatio-temporal land use regression model. We assessed cognition using the Mini-Mental State Examination (MMSE), a test of global function, and performance on a battery of other tests, covering a wide range of domains. We investigated whether variants of HFE C282Y and H63D modified the association between BC and having a low MMSE score using logistic models with generalized estimating equations and multiplicative interaction terms. Similarly, we assessed whether HFE variants modified the association between BC and performance on the cognitive battery using linear mixed models with multiplicative interaction terms.
Our results suggest modification of the BC-cognition association by HFE C282Y, although the test of interaction did not achieve statistical significance. In multivariable-adjusted models, participants who lacked a HFE C282Y variant (CC) exhibited an adverse association between BC and total cognition z-score (beta for a doubling in BC concentration: -0.061, 95% CI: -0.115, -0.007), while we did not observe an association in participants with at least one variant genotype (CY or YY) (beta for a doubling in BC concentration: 0.073, 95% CI: -0.081, 0.228; p-value for interaction: 0.11). The pattern of association was similar for analyses considering performance on the Mini-Mental State Examination. There was little evidence to support effect modification of the BC-cognition association by the HFE H63D genotype.
Our data suggest that older adults who lack an HFE C282Y variant may be more susceptible to an adverse effect of traffic-related air pollution exposure on cognition. This finding and the proposed biological mechanism require confirmation.
Aging; Black carbon; Cognitive dysfunction; Epidemiology; Particulate matter; HFE; Hemochromatosis; Gene-environment interaction; Susceptible group
Low-level environmental cadmium exposure and neurotoxicity has not been well studied in adults. Our goal was to evaluate associations between neurocognitive exam scores and a biomarker of cumulative cadmium exposure among adults in the Third National Health and Nutrition Examination Survey (NHANES III).
NHANES III is a nationally representative cross-sectional survey of the U.S. population conducted between 1988 and 1994. We analyzed data from a subset of participants, age 20–59, who participated in a computer-based neurocognitive evaluation. There were four outcome measures: the Simple Reaction Time Test (SRTT: visual motor speed), the Symbol Digit Substitution Test (SDST: attention/perception), the Serial Digit Learning Test (SDLT) trials-to-criterion, and the SDLT total-error-score (SDLT-tests: learning recall/short-term memory). We fit multivariable-adjusted models to estimate associations between urinary cadmium concentrations and test scores.
5662 participants underwent neurocognitive screening, and 5572 (98%) of these had a urinary cadmium level available. Prior to multivariable-adjustment, higher urinary cadmium concentration was associated with worse performance in each of the 4 outcomes. After multivariable-adjustment most of these relationships were not significant, and age was the most influential variable in reducing the association magnitudes. However among never-smokers with no known occupational cadmium exposure the relationship between urinary cadmium and SDST score (attention/perception) was significant: a 1 μg/L increase in urinary cadmium corresponded to a 1.93% (95%CI: 0.05, 3.81) decrement in performance.
These results suggest that higher cumulative cadmium exposure in adults may be related to subtly decreased performance in tasks requiring attention and perception, particularly among those adults whose cadmium exposure is primarily though diet (no smoking or work based cadmium exposure). This association was observed among exposure levels that have been considered to be without adverse effects and these levels are common in U.S. adults. Thus further research into the potential neurocognitive effects of cadmium exposure is warranted. Because cumulative cadmium exposure may mediate some of the effects of age and smoking on cognition, adjusting for these variables may result in the underestimation of associations with cumulative cadmium exposure. Prospective studies that include never-smokers and non-occupationally exposed individuals are needed to clarify these issues.
Cadmium; Neurocognitive; Neuropsychological; NES2; NHANES; Attention; Smoking; Metals; Aging; Cognitive
Purpose of Review
A systematic approach to studying gene-environment interaction can have immediate impact on our understanding of how environmental factors induce developmental disease and toxicity and provide biological insight for potential treatment and prevention measures.
Because DNA sequence is static, genetic studies typically are not conducted prospectively. This limits the ability to incorporate environmental data into an analysis, as such data is usually collected cross-sectionally. Prospective environmental data collection could account for the role of critical windows of susceptibility that likely corresponds to the expression of specific genes and gene pathways. The use of large scale genomic platforms to discover genetic variants that modify environmental exposure in conjunction with a priori planned replication studies would reduce the number of false positive results.
Using a genome-wide approach, combined with a prospective longitudinal of environmental exposure at critical developmental windows is the optimal design for gene-environment interaction research. This approach would discover susceptibility variants, then validate the findings in an independent sample of children. Designs which combine the strengths and methodologies of each field will yield data which can account for both genetic variability and the role of critical developmental windows in the etiology of childhood disease and development.
genetics; pediatrics; prenatal environment
Both nurture (environmental) and nature (genetic factors) play an important role in human disease etiology. Traditionally, these effects have been thought of as independent. This perspective is ill informed for non-mendelian complex disorders which result as an interaction between genetics and environment. To understand health and disease we must study how nature and nurture interact. Recent advances in human genomics and high-throughput biotechnology make it possible to study large numbers of genetic markers and gene products simultaneously to explore their interactions with environment. The purpose of this review is to discuss design and analytic issues for gene-environment interaction studies in the “-omics” era, with a focus on environmental and genetic epidemiological studies. We present an expanded environmental genomic disease paradigm. We discuss several study design issues for gene-environmental interaction studies, including confounding and selection bias, measurement of exposures and genotypes. We discuss statistical issues in studying gene-environment interactions in different study designs, such as choices of statistical models, assumptions regarding biological factors, and power and sample size considerations, especially in genome-wide gene-environment studies. Future research directions are also discussed.
Gene-environment; Interactions; Expanded environmental genomic disease paradigm; Critical developmental windows; Genome-wide; Epigenetics
Pessimism, a general tendency toward negative expectancies, is a risk factor for depression and also heart disease, stroke, and reduced cancer survival. There is evidence that individuals with higher lead exposure have poorer health. However, low socioeconomic status (SES) is linked with higher lead levels and greater pessimism, and it is unclear whether lead influences psychological functioning independently of other social factors. The authors considered interrelations among childhood and adult SES, lead levels, and psychological functioning in data collected on 412 Boston area men between 1991 and 2002 in a subgroup of the VA Normative Aging Study. Pessimism was measured by using the Life Orientation Test. Cumulative (tibia) lead was measured by x-ray fluorescence. Structural equation modeling was used to quantify the relations as mediated by childhood and adult SES, controlling for age, health behaviors, and health status. An interquartile range increase in lead quartile was associated with a 0.37 increase in pessimism score (P < 0.05). Low childhood and adult SES were related to higher tibia lead levels, and both were also independently associated with higher pessimism. Lead maintained an independent association with pessimism even after childhood and adult SES were considered. Results demonstrate an interrelated role of lead burden and SES over the life course in relation to psychological functioning in older age.
depression; lead; metals; orientation; psychology; socioeconomic factors
To investigate the effects of pre- and postnatal lead exposure and polymorphisms in dopamine metabolism genes on neurocognitive development of Mexican children at 24 (n=220) and 48 months (n=186) of age.
We genotyped the dopamine transporter gene (DAT1; SLC6A3) variable nucleotide tandem repeat, and the dopamine receptor D2 (DRD2) Taq 1A single nucleotide polymorphism. Children were assessed at 24 mo with Bayley Scales of Infant Development (MDI, PDI) and at 48 mo with McCarthy Scales of Children’s Abilities.
Lead concentration (BLL) in umbilical cord was 6.6±3.3 μg/dL (measured in 1995-96), 8.1±4.4 μg/dL at 24, and 8.1±3.6 μg/dL at 48 months. Cord BLL was negatively associated with MDI (p<0.01) and PDI (p<0.1) but not McCarthy scores. The 48- but not 24-month BLL was negatively associated with children’s scores. Children with DRD2 TT genotype (variant) scored higher than those with CC genotype (wild type) on MDI and McCarthy memory scale. Neither polymorphism modified the relationship between BLL (either pre or post-natal) and neurocognitive development.
Lead exposure was adversely, whereas the DRD2 Taq 1A TT variant was positively associated with neurocognitive measures. We found no evidence of gene-environment interactions on developmental outcomes in early childhood.
Cord blood lead; postnatal lead exposure; DAT1; DRD2; gene polymorphisms; Mexico; child development
Children living near hazardous waste sites may be exposed to environmental contaminants, yet few studies have conducted multi-media exposure assessments, including residential environments where children spend most of their time. We sampled yard soil, house dust, and particulate matter with aerodynamic diameter <2.5 in 59 homes of young children near an abandoned mining area and analyzed samples for lead (Pb), zinc (Zn), cadmium (Cd), arsenic (As), and manganese (Mn). In over half of the homes, dust concentrations of Pb, Zn, Cd, and As were higher than those in soil. Proximity to mine waste (chat) piles and the presence of chat in the driveway significantly predicted dust metals levels. Homes with both chat sources had Pb, Zn, Cd, and As dust levels two to three times higher than homes with no known chat sources after controlling for other sources. In contrast, Mn concentrations in dust were consistently lower than in soil and were not associated with chat sources. Mn dust concentrations were predicted by soil concentrations and occupant density. These findings suggest that nearby outdoor sources of metal contaminants from mine waste may migrate indoors. Populations farther away from the mining site may also be exposed if secondary uses of chat are in close proximity to the home.
house dust; indoor air pollution; metals; mine waste; residential exposures; Tar Creek Superfund Site
To find the best lead exposure assessment marker for children.
We recruited 11 children, calculated a cumulative blood lead index (CBLI) for the children, measured their concurrent BLL, assessed their development, and measured their bone lead level.
Nine of 11 children had clinically significant neurodevelopment problems. CBLI and current blood lead level, but not the peak lead level, were significantly or marginally negatively associated with the full-scale IQ score.
Lead exposure at younger age significantly impacts a child’s later neurodevelopment. CBLI may be a better predictor of neurodevelopment than are current or peak blood lead levels.
Heavy metal toxicity; neurological disease; environmental pollution/ecotoxicology
Bone lead is a cumulative measure of lead exposure that can also be remobilized. We examined repeated measures of bone lead over 11 years to characterize long-term changes and identify predictors of tibia and patella lead stores in an elderly male population.
Lead was measured every 3–5 years by k-x-ray fluorescence and mixed-effect models with random effects were used to evaluate change over time.
554 participants provided up to 4 bone lead measurements. Final models predicted a −1.4% annual decline (95%CI: −2.2,−0.7) for tibia lead and piecewise linear model for patella with an initial decline of 5.1% per year (95%CI: −6.2,−3.9) during the first 4.6 years but no significant change thereafter (−0.4% (95% CI: −2.4, 1.7)).
These results suggest that bone lead half-life may be longer than previously reported.
Background: Arsenic is an epigenetic toxicant and could influence fetal developmental programming.
Objectives: We evaluated the association between arsenic exposure and DNA methylation in maternal and umbilical cord leukocytes.
Methods: Drinking-water and urine samples were collected when women were at ≤ 28 weeks gestation; the samples were analyzed for arsenic using inductively coupled plasma mass spectrometry. DNA methylation at CpG sites in p16 (n = 7) and p53 (n = 4), and in LINE-1 and Alu repetitive elements (3 CpG sites in each), was quantified using pyrosequencing in 113 pairs of maternal and umbilical blood samples. We used general linear models to evaluate the relationship between DNA methylation and tertiles of arsenic exposure.
Results: Mean (± SD) drinking-water arsenic concentration was 14.8 ± 36.2 μg/L (range: < 1–230 μg/L). Methylation in LINE-1 increased by 1.36% [95% confidence interval (CI): 0.52, 2.21%] and 1.08% (95% CI: 0.07, 2.10%) in umbilical cord and maternal leukocytes, respectively, in association with the highest versus lowest tertile of total urinary arsenic per gram creatinine. Arsenic exposure was also associated with higher methylation of some of the tested CpG sites in the promoter region of p16 in umbilical cord and maternal leukocytes. No associations were observed for Alu or p53 methylation.
Conclusions: Exposure to higher levels of arsenic was positively associated with DNA methylation in LINE-1 repeated elements, and to a lesser degree at CpG sites within the promoter region of the tumor suppressor gene p16. Associations were observed in both maternal and fetal leukocytes. Future research is needed to confirm these results and determine if these small increases in methylation are associated with any health effects.
Alu; arsenic; developmental programming; DNA methylation; environmental exposures; epigenetics; in utero exposure; LINE-1; p16; p53
Background: Low-level environmental cadmium exposure in children may be associated with adverse neurodevelopmental outcomes.
Objective: Our aim was to evaluate associations between urinary cadmium concentration and reported learning disability (LD), special education utilization, and attention deficit hyperactivity disorder (ADHD) in U.S. children using National Health and Nutrition Examination Survey (NHANES) data.
Methods: We analyzed data from a subset of participants in NHANES (1999–2004) who were 6–15 years of age and had spot urine samples analyzed for cadmium. Outcomes were assessed by parent or proxy-respondent report. We fit multivariable-adjusted logistic regression models to estimate associations between urinary cadmium and the outcomes.
Results: When we compared children in the highest quartile of urinary cadmium with those in the lowest quartile, odds ratios adjusted for several potential confounders were 3.21 [95% confidence interval (CI): 1.43, 7.17] for LD, 3.00 (95% CI: 1.12, 8.01) for special education, and 0.67 (95% CI: 0.28, 1.61) for ADHD. There were no significant interactions with sex, but associations with LD and special education were somewhat stronger in males, and the trend in the ADHD analysis was only evident among those with blood lead levels above the median.
Conclusions: These findings suggest that children who have higher urinary cadmium concentrations may have increased risk of both LD and special education. Importantly, we observed these associations at exposure levels that were previously considered to be without adverse effects, and these levels are common among U.S. children.
attention deficit hyperactivity disorder; cadmium; learning disability; neurodevelopment; neuropsychological development; NHANES; risk assessment; special education
Background: Lead exposure has been associated with cardiovascular disease (CVD) in animal and human studies. However, the mechanisms of action have not been fully elucidated. We therefore examined the relationship between lead and multiple biomarkers of CVD.
Methods: Participants were older men from the Normative Aging Study without preexisting coronary heart disease, diabetes, or active infection at baseline (n = 426). Serum biomarkers included lipid profile [total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides] and inflammatory markers [C-reactive protein, intercellular adhesion molecule-1, interleukin-6, and tumor necrosis factor receptor-2 (TNF-R2)]. We measured lead in blood and in bone by K-shell X-ray fluorescence. In this sample, 194 men (44.3%) had two or more repeated measures, resulting in 636 observations for analysis. We conducted analyses using mixed effects models with random subject intercepts.
Results: Lead levels were associated with several CVD biomarkers, including levels of TNF-R2 and lipid markers. Specifically, in multivariable models, a 50% increase in blood lead level was associated with 26% increased odds of high TNF-R2 levels (> 5.52 ng/mL; odds ratio = 1.26; 95% confidence interval: 1.09, 1.45). There were positive associations of blood lead level with total cholesterol and HDL levels, and these associations were more evident when modeled as continuous outcomes than when categorized using clinically relevant cut points. In addition, longitudinal analyses indicated a significant increase in TNF-R2 levels over time to be associated with high blood lead level at the preceding visit.
Conclusions: Blood lead level may be related with CVD in healthy older men through its association with TNF-R2 levels. In addition, the magnitude of the association of blood lead level with TNF-R2 level increased with age in the study population.
aging; biomarkers; cardiovascular; cholesterol; inflammation; lead; metals
Background: Lead exposure in adults is associated with hypertension. Altered prenatal nutrition is associated with subsequent risks of adult hypertension, but little is known about whether prenatal exposure to toxicants, such as lead, may also confer such risks.
Objectives: We investigated the relationship of prenatal lead exposure and blood pressure (BP) in 7- to 15-year-old boys and girls.
Methods: We evaluated 457 mother–child pairs, originally recruited for an environmental birth cohort study between 1994 and 2003 in Mexico City, at a follow-up visit in 2008–2010. Prenatal lead exposure was assessed by measurement of maternal tibia and patella lead using in vivo K-shell X-ray fluorescence and cord blood lead using atomic absorption spectrometry. BP was measured by mercury sphygmomanometer with appropriate-size cuffs.
Results: Adjusting for relevant covariates, maternal tibia lead was significantly associated with increases in systolic BP (SBP) and diastolic BP (DBP) in girls but not in boys (p-interaction with sex = 0.025 and 0.007 for SBP and DBP, respectively). Among girls, an interquartile range increase in tibia lead (13 μg/g) was associated with 2.11-mmHg [95% confidence interval (CI): 0.69, 3.52] and 1.60-mmHg (95% CI: 0.28, 2.91) increases in SBP and DBP, respectively. Neither patella nor cord lead was associated with child BP.
Conclusions: Maternal tibia lead, which reflects cumulative environmental lead exposure and a source of exposure to the fetus, is a predisposing factor to higher BP in girls but not boys. Sex-specific adaptive responses to lead toxicity during early-life development may explain these differences.
blood pressure; children; lead; prenatal exposure; sex
Background: Arsenic, cadmium, mercury, and lead are associated with cardiovascular disease in epidemiologic research. These associations may be mediated by direct effects of the metals on blood pressure (BP) elevation. Manganese is associated with cardiovascular dysfunction and hypotension in occupational cohorts.
Objectives: We hypothesized that chronic arsenic, cadmium, mercury, and lead exposures elevate BP and that manganese lowers BP.
Methods: We conducted a cross-sectional analysis of associations between toenail metals and BP among older men from the Normative Aging Study (n = 639), using linear regression and adjusting for potential confounders.
Results: An interquartile range increase in toenail arsenic was associated with higher systolic BP [0.93 mmHg; 95% confidence interval (CI): 0.25, 1.62] and pulse pressure (0.76 mmHg; 95% CI: 0.22, 1.30). Positive associations between arsenic and BP and negative associations between manganese and BP were strengthened in models adjusted for other toenail metals.
Conclusions: Our findings suggest associations between BP and arsenic and manganese. This may be of public health importance because of prevalence of both metal exposure and cardiovascular disease. Results should be interpreted cautiously given potential limitations of toenails as biomarkers of metal exposure.
arsenic; blood pressure; cadmium; epidemiology; lead; manganese; mercury; metals