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1.  Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function 
Neurotoxicology  2013;0:10.1016/j.neuro.2013.08.002.
Background
Glutathione-S-transferase gene (GST) polymorphisms can result in variable ability of these enzymes to remove electrophilic substrates. We investigated whether the GSTP1 Val105 and GSTM1 deletion polymorphisms modify the lead-cognitive function association.
Methods
We used repeated measures analysis to compare the association between cumulative lead biomarkers—bone lead measured using K-shell X-Ray Fluorescence—and Mini-Mental State Exam (MMSE) score by GST variants, adjusted for covariates, among Normative Aging Study participants, a Boston-based prospective cohort of men. We had complete data for 698 men (providing 1292 observations) for GSTM1 analyses and 595 men (providing 1142 observations) for GSTP1 analyses.
Results
A 15 μg/g higher tibia lead concentration (interquartile range of tibia lead) was associated with a 0.24 point decrement in MMSE score among GSTP1 Val105 variant carriers, which was significantly stronger than the association among men with only wild-type alleles (p=0.01). The association among GSTP1 Val105 carriers was comparable to that of 3 years of age in baseline MMSE scores. The association between tibia lead and MMSE score appeared progressively steeper in participants with increasingly more GSTP1 Val105 alleles. A modest association between tibia lead and lower MMSE score was seen among participants with the GSTM1 deletion polymorphism. Neither of the glutathione S-transferase variants was independently associated with cognitive function, nor with lead biomarker measures. The results pertaining to patella lead were similar to those observed for tibia lead.
Conclusion
Our results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.
doi:10.1016/j.neuro.2013.08.002
PMCID: PMC3844089  PMID: 23958642
Lead; Glutathione S-transferase; Cognitive function; Environmental exposure; Gene-environment interaction
2.  Maternal iron metabolism gene variants modify umbilical cord blood lead levels by gene-environment interaction: a birth cohort study 
Environmental Health  2014;13(1):77.
Background
Given the relationship between iron metabolism and lead toxicokinetics, we hypothesized that polymorphisms in iron metabolism genes might modify maternal-fetal lead transfer. The objective of this study was to determine whether maternal and/or infant transferrin (TF) and hemochromatosis (HFE) gene missense variants modify the association between maternal blood lead (MBL) and umbilical cord blood lead (UCBL).
Methods
We studied 476 mother-infant pairs whose archived blood specimens were genotyped for TF P570S, HFE H63D and HFE C282Y. MBL and UCBL were collected within 12 hours of delivery. Linear regression models were used to examine the association between log-transformed MBL and UCBL, examine for confounding and collinearity, and explore gene-environment interactions.
Results
The geometric mean MBL was 0.61 μg/dL (range 0.03, 3.2) and UCBL 0.42 (<0.02, 3.9). Gene variants were common with carrier frequencies ranging from 12-31%; all were in Hardy-Weinberg equilibrium. In an adjusted linear regression model, log MBL was associated with log UCBL (β = 0.92, 95% CI: 0.82, 1.03; p < 0.01) such that a 1% increase in MBL was associated with a 0.92% increase in UCBL among infants born to wild-type mothers. In infants born to C282Y variants, however, a 1% increase in MBL is predicted to increase UCBL 0.65% (βMain Effect = −0.002, 95% CI: −0.09, −0.09; p = 0.97; βInteraction = −0.27, 95% CI: −0.52, −0.01; p = 0.04), representing a 35% lower placental lead transfer among women with MBL 5 μg/dL.
Conclusions
Maternal HFE C282Y gene variant status is associated with greater reductions in placental transfer of lead as MBL increases. The inclusion of gene-environment interaction in risk assessment models may improve efforts to safeguard vulnerable populations.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-069X-13-77) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-069X-13-77
PMCID: PMC4271345  PMID: 25287020
Hemochromatosis gene; C282Y; H63D; Lead; Pediatric; Polymorphism; Prenatal; P570S; Transferrin gene
3.  Racial/ethnic and sociodemographic factors associated with micronutrient intakes and inadequacies among pregnant women in an urban US population 
Public health nutrition  2013;17(9):1960-1970.
Objective
To assess sociodemographic correlates of micronutrient intakes from food and dietary supplements in an urban, ethnically diverse sample of pregnant women in the USA.
Design
Cross-sectional analyses of data collected using a validated semi-quantitative FFQ. Associations between racial, ethnic and sociodemographic factors and micronutrient intakes were examined using logistic regression controlling for pre-pregnancy BMI, maternal age and smoking status.
Setting
Prenatal clinics, Boston, MA, USA.
Subjects
Analyses included pregnant women (n 274) in the PRogramming of Intergenerational Stress Mechanisms (PRISM) study, an urban longitudinal cohort designed to examine how stress influences respiratory health in children when controlling for other environmental exposures (chemical stressors, nutrition).
Results
High frequencies of vitamin E (52%), Mg (38%), Fe (57%) and vitamin D (77%) inadequacies as well as suboptimal intakes of choline (95 %) and K (99%) were observed. Factors associated with multiple antioxidant inadequacies included being Hispanic or African American, lower education and self-reported economic-related food insecurity. Hispanics had a higher prevalence of multiple methyl-nutrient inadequacies compared with African Americans; both had suboptimal betaine intakes and higher odds for vitamin B6 and Fe inadequacies compared with Caucasians. Nearly all women (98%) reported Na intakes above the tolerable upper limit; excessive intakes of Mg (35 %), folate (37 %) and niacin (38 %) were also observed. Women reporting excessive intakes of these nutrients were more likely Caucasian or Hispanic, more highly educated, US-born and did not report food insecurity.
Conclusions
Racial/ethnic and other sociodemographic factors should be considered when tailoring periconceptional dietary interventions for urban ethnic women in the USA.
doi:10.1017/S1368980013003224
PMCID: PMC4071127  PMID: 24476840
Micronutrients; Pregnancy; Disparities
4.  Effect modification by Transferrin C2 polymorphism on lead exposure, hemoglobin levels, and IQ 
Neurotoxicology  2013;38:17-22.
Background
Iron deficiency and lead exposure remain significant public health issues in many parts of the world and are both independently associated with neurocognitive deficits. Polymorphisms in iron transport pathways have been shown to modify the absorption and toxicity of lead.
Objective
We hypothesized that the transferrin (TF) C2 polymorphism modifies the effects of lead and hemoglobin on intelligence.
Methods
Children aged 3–7 years (N=708) were enrolled from 12 primary schools in Chennai, India. The Binet-Kamat Scale of Intelligence were administered to ascertain intelligence quotient (IQ). Venous blood was analyzed for lead and hemoglobin levels. Genotyping for the TF C2 polymorphism (rs1049296) was carried out using a MassARRAY iPLEXTM platform. Stratified analyses and interaction models, using generalized estimating equations, were examined to explore interactions between lead, hemoglobin, and TF C2 categories.
Results
A one-unit increase in log blood lead and 1 g/dl higher hemoglobin was associated with −7.7 (95% CI: −13.6, −1.8) and 1.7 (95% CI 1.4, 2.1) IQ points, respectively, among children carrying the C2 variant. In comparison, among children who had the homozygous wildtype allele, the same increment of lead and hemoglobin were associated with -−2.1(95% CI: −6.5, 2.4) and 2.8(95% CI:1.5, 4.0) IQ points, respectively. There was a significant interaction between lead (p=0.04) and hemoglobin (p=0.07) with the C2 variant.
Conclusion
Children who carry the TF C2 variant may be more susceptible to the neurotoxic effects of lead exposure and less protected by higher levels of hemoglobin.
doi:10.1016/j.neuro.2013.05.005
PMCID: PMC3770761  PMID: 23732512
lead; hemoglobin; iron; transferrin; intelligence quotient (IQ); genotype
5.  Contaminated Turmeric Is a Potential Source of Lead Exposure for Children in Rural Bangladesh 
Background. During the conduct of a cohort study intended to study the associations between mixed metal exposures and child health outcomes, we found that 78% of 309 children aged 20–40 months evaluated in the Munshiganj District of Bangladesh had blood lead concentrations ≥5 µg/dL and 27% had concentrations ≥10 µg/dL. Hypothesis. Environmental sources such as spices (e.g., turmeric, which has already faced recalls in Bangladesh due to high lead levels) may be a potential route of lead exposure. Methods. We conducted visits to the homes of 28 children randomly selected from among high and low blood lead concentration groups. During the visits, we administered a structured questionnaire and obtained soil, dust, rice, and spice samples. We obtained water samples from community water sources, as well as environmental samples from neighborhood businesses. Results. Lead concentrations in many turmeric samples were elevated, with lead concentrations as high as 483 ppm. Analyses showed high bioaccessibility of lead. Conclusions. Contamination of turmeric powder is a potentially important source of lead exposure in this population.
doi:10.1155/2014/730636
PMCID: PMC4158309  PMID: 25214856
6.  Relationships between lead biomarkers and diurnal salivary cortisol indices in pregnant women from Mexico City: a cross-sectional study 
Environmental Health  2014;13:50.
Background
Lead (Pb) exposure during pregnancy may increase the risk of adverse maternal, infant, or childhood health outcomes by interfering with hypothalamic-pituitary-adrenal-axis function. We examined relationships between maternal blood or bone Pb concentrations and features of diurnal cortisol profiles in 936 pregnant women from Mexico City.
Methods
From 2007–11 we recruited women from hospitals/clinics affiliated with the Mexican Social Security System. Pb was measured in blood (BPb) during the second trimester and in mothers’ tibia and patella 1-month postpartum. We characterized maternal HPA-axis function using 10 timed salivary cortisol measurements collected over 2-days (mean: 19.7, range: 14–35 weeks gestation). We used linear mixed models to examine the relationship between Pb biomarkers and cortisol area under the curve (AUC), awakening response (CAR), and diurnal slope.
Results
After adjustment for confounders, women in the highest quintile of BPb concentrations had a reduced CAR (Ratio: −13%; Confidence Interval [CI]: −24, 1, p-value for trend < 0.05) compared to women in the lowest quintile. Tibia/patella Pb concentrations were not associated with CAR, but diurnal cortisol slopes were suggestively flatter among women in the highest patella Pb quantile compared to women in the lowest quantile (Ratio: 14%; CI: −2, 33). BPb and bone Pb concentrations were not associated with cortisol AUC.
Conclusions
Concurrent blood Pb levels were associated with cortisol awakening response in these pregnant women and this might explain adverse health outcomes associated with Pb. Further research is needed to confirm these results and determine if other environmental chemicals disrupt hypothalamic-pituitary-adrenal-axis function during pregnancy.
doi:10.1186/1476-069X-13-50
PMCID: PMC4068833  PMID: 24916609
Lead; Cortisol; Epidemiology; Pregnancy
7.  Determining Prenatal, Early Childhood and Cumulative Long-Term Lead Exposure Using Micro-Spatial Deciduous Dentine Levels 
PLoS ONE  2014;9(5):e97805.
The aim of this study was to assess the validity of micro-spatial dentine lead (Pb) levels as a biomarker for accurately estimating exposure timing over the prenatal and early childhood periods and long-term cumulative exposure to Pb. In a prospective pregnancy cohort sub-sample of 85 subjects, we compared dentine Pb levels measured using laser ablation-inductively coupled plasma mass spectrometry with Pb concentrations in maternal blood collected in the second and third trimesters, maternal bone, umbilical cord blood, and childhood serial blood samples collected from the ages of 3 months to ≥6 years. We found that Pb levels (as 208Pb:43Ca) in dentine formed at birth were significantly associated with cord blood Pb (Spearman ρ = 0.69; n = 27; p<0.0001). The association of prenatal dentine Pb with maternal patella Pb (Spearman ρ = 0.48; n = 59; p<0.0001) was stronger than that observed for tibia Pb levels (Spearman ρ = 0.35; n = 41; p<0.03). When assessing postnatal exposure, we found that Pb levels in dentine formed at 3 months were significantly associated with Pb concentrations in children’s blood collected concurrently (Spearman ρ = 0.64; n = 55; p<0.0001). We also found that mean Pb concentrations in secondary dentine (that is formed from root completion to tooth shedding) correlated positively with cumulative blood lead index (Spearman ρ = 0.38; n = 75; p<0.0007). Overall, our results support that micro-spatial measurements of Pb in dentine can be reliably used to reconstruct Pb exposure timing over the prenatal and early childhood periods, and secondary dentine holds the potential to estimate long-term exposure up to the time the tooth is shed.
doi:10.1371/journal.pone.0097805
PMCID: PMC4026445  PMID: 24841926
8.  Ambient particulate air pollution and microRNAs in elderly men 
Background
Ambient particulate matter (PM) has been associated with mortality and morbidity for cardiovascular disease (CVD). MicroRNAs control gene expression at a post-transcriptional level. Altered microRNA expression has been reported in processes related to CVD and PM exposure, e.g. systemic inflammation, endothelial dysfunction and atherosclerosis. Polymorphisms in microRNA-related genes could influence response to PM.
Methods
We investigated the association of exposure to ambient particles in several time windows (4-hours to 28-days moving averages) and blood-leukocyte expression changes in fourteen candidate microRNAs, in 153 elderly males from the Normative Aging Study (examined 2005–2009). Potential effect modification by six single nucleotide polymorphisms (SNPs) in three microRNA-related genes was investigated. Fine PM (PM2.5), black carbon, organic carbon and sulfates were measured at a stationary ambient monitoring site. Linear regression models, adjusted for potential confounders, were used to assess effects of particles and SNP-by-pollutant interaction. An in silico pathways analysis was performed on target genes of miRNAs associated with the pollutants.
Results
We found a negative association for pollutants in all moving averages and miR-1, -126, -135a, -146a, -155, -21, -222 and -9. The strongest associations were observed with the 7-day moving averages for PM2.5 and black carbon and with the 48-hour moving averages for organic carbon. The association with sulfates was stable across the moving averages. The in silico pathway analysis identified 18 pathways related to immune response shared by at least two miRNAs; in particular, the “HMGB1/RAGE signaling pathway” was shared by miR-126, -146a, -155, -21 and -222.
No important associations were observed for miR-125a-5p, -125b, -128, -147, -218 and -96. We found significant SNP-by-pollutant interactions for rs7813, rs910925 and rs1062923 in GEMIN4 and black carbon and PM2.5 for miR-1, -126, -146a, -222 and -9, and for rs1640299 in DGCR8 and SO42− for miR-1 and -135a.
Conclusions
Exposure to ambient particles could cause a downregulation of microRNAs involved in processes related to PM exposure. Polymorphisms in GEMIN4 and DGCR8 could modify these associations.
doi:10.1097/EDE.0000000000000026
PMCID: PMC3977338  PMID: 24257509
9.  Association between birth weight and DNA methylation of IGF2, glucocorticoid receptor and repetitive elements LINE-1 and Alu 
Epigenomics  2013;5(3):271-281.
Aim
We examined the association between birth weight and methylation in the imprinted IGF/H19 loci, the nonimprinted gene NR3C1 and repetitive element DNA (LINE-1 and Alu).
Materials & methods
We collected umbilical cord venous blood from 219 infants born in Mexico City (Mexico) as part of a prospective birth cohort study and analyzed DNA methylation using pyrosequencing.
Results
Birth weight was not associated with DNA methylation of the regions studied. One of the CpG dinucleotides in the IGF2 imprinting control region (ICR)1 includes a potential C–T SNP. Among individuals with an absence of methylation at this site, probably due to a paternally inherited T allele, birth weight was associated with mean methylation status of both IGF2 ICR1 and ICR2. However, this association would not have survived adjustment for multiple testing.
Conclusion
While we did not detect an association between DNA methylation and birth weight, our study suggests a potential gene–epigene interaction between a T allele in the IGF2 ICR1 and methylation of ICRs of IGF2, and fetal growth.
doi:10.2217/epi.13.24
PMCID: PMC3787720  PMID: 23750643
Alu; birth weight; DNA methylation; fetal growth; glucocorticoid receptor; IGF2; imprinting; LINE-1; NR3C1; SNP
10.  Air Pollution and Homocysteine: More Evidence that Oxidative Stress-related Genes Modify Effects of Particulate Air Pollution 
Epidemiology (Cambridge, Mass.)  2010;21(2):198-206.
Background
Ambient particles are associated with cardiovascular events, and recently with total plasma homocysteine. High total plasma homocysteine is a risk for human health. However, the biological mechanisms are not fully understood. One of putative pathways is through oxidative stress. We aimed to examine whether associations of PM2.5 and black carbon with homocysteine were modified by genotypes including HFE H63D, C282Y, CAT (rs480575, rs1001179, rs2284367 and rs2300181), NQO1 (rs1800566), GSTP1 I105V, GSTM1, GSTT1(deletion vs non-deletion) and HMOX-1 (any short vs both long). We attempted to replicate identified genes in an analysis of heart rate variability, and in other outcomes reported in the literature.
Methods
Study subjects were 1000 white non-Hispanic men in the Boston area, participating in a cohort study of aging. PM2.5, black carbon, total plasma homocysteine and other covariates were measured at several points in time between 1995 and 2006. We fit mixed models to examine effect modification of genes on associations of pollution with total plasma homocysteine.
Results
Interquartile range (IQR) increases in PM2.5 and black carbon (7-day moving averages) were associated with 1.5% (95% confidence interval = 0.2% to 2.8%) and 2.2% (0.6% to 3.9%) increases in total plasma homocysteine, respectively. GSTT1 and HFE C282Y modified effects of black carbon on total plasma homocysteine, and HFE C282Y and CAT (rs2300181) modified effects of PM2.5 on homocysteine. Several genotypes marginally modified effects of PM2.5 and black carbon on various endpoints. All genes with significant interactions with particulate air pollution had modest main effects on total plasma homocysteine.
Conclusions
Effects of PM2.5 and black carbon on various endpoints appeared to be mediated by genes related to oxidative stress pathways.
doi:10.1097/EDE.0b013e3181cc8bfc
PMCID: PMC3939788  PMID: 20110814
11.  Cumulative exposure to lead and cognition in persons with Parkinson’s disease 
Background
Dementia is an important consequence of Parkinson’s disease (PD), with few known modifiable risk factors. Cumulative exposure to lead, at levels experienced in the community, may exacerbate PD-related neural dysfunction, resulting in impaired cognition.
Methods
Among 101 persons with PD (“cases”) and, separately, 50 persons without PD (“controls”), we evaluated cumulative lead exposure, gauged via tibia and patella bone lead concentrations, in relation to cognitive function, assessed using a telephone battery developed and validated in a separate sample of PD patients. We also assessed the interaction between lead and case-control status.
Results
After multivariable adjustment, higher tibia bone lead concentration among PD cases was associated with worse performance on all of the individual telephone tests. In particular, tibia lead levels corresponded to significantly worse performance on a telephone analogue of the Mini-Mental State Examination and tests of working memory and attention. Moreover, higher tibia bone lead concentration was associated with significantly worse global composite score encompassing all the cognitive tests (P=0.04). The magnitude of association per standard deviation increment in tibia bone lead level was equivalent to the difference in global scores among controls in our study who were about seven years apart in age. The tibia lead-cognition association was notably stronger within cases than within controls (Pdifference=0.06). Patella bone lead concentration was not consistently associated with performance on the tests.
Conclusions
These data provide evidence suggesting that cumulative exposure to lead may result in worsened cognition among persons with PD.
doi:10.1002/mds.25247
PMCID: PMC3581753  PMID: 23143985
lead exposure; cognitive function; Parkinson’s disease
12.  Association between blood pressure and DNA methylation of retrotransposons and pro-inflammatory genes 
Background Methylation of deoxyribonucleic acid (DNA) is an epigenetic regulator of gene expression that changes with age, but its contribution to aging-related disorders, including high blood pressure (BP), is still largely unknown. We examined the relation of BP to the methylation of retrotransposon sequences of DNA and of selected candidate genes.
Methods This investigation included 789 elderly participants in the Normative Aging Study, ranging in age from 55 to 100 years, who had longitudinal measurements of DNA methylation. In these subjects’ DNA we measured the proportion of methylated sites in retrotransposable sequences and in pro-inflammatory genes, expressed as the percent of 5-methylated cytosines (%5mC) among all cytosines. From one to four methylation measurements were made for each subject between 1999 and 2009. We fit mixed-effects models, using repeated measures of BP as the outcome and DNA methylation as the explanatory variable, adjusting for confounding variables. We also fit a Bayesian mixed-effects structural equation model to account for heterogeneity in the effects of methylation sites within each gene.
Results An increase in inter-quartile range (IQR) in the methylation of Alu elements was associated with an increase of 0.97 mm Hg in diastolic blood pressure (DBP) (95% CI 0.32–1.57), but no such association was observed for long interspersed nuclear element-1 (LINE-1). We also found positive associations between DBP and methylation of the genes for toll-like receptor 2 (TLR2) and inducible nitric oxide synthase (iNOS), and a negative association between DBP and methylation of the gene for interferon-γ (IFN-γ). Associations between methylation and systolic blood pressure (SBP) were weaker than those between methylation and DBP. Bayesian mixed-effects structural equation model results were similar for both DBP and SBP models.
Conclusions The results of our study suggest that changes in DNA methylation of some pro-inflammatory genes and retrotransposable elements are related to small changes in BP.
doi:10.1093/ije/dys220
PMCID: PMC3600626  PMID: 23508416
Epigenetics; DNA methylation; blood pressure; inflammation; Bayesian model
13.  Interpersonal Trauma Exposure and Cognitive Development in Children to Age 8 Years: A Longitudinal Study 
Background
Childhood trauma exposure has been associated with deficits in cognitive functioning. The influence of timing of exposure on the magnitude and persistence of deficits is not well understood. The impact of exposure in early development has been especially under-investigated. This study examined the impact of interpersonal trauma exposure (IPT) in the first years of life on childhood cognitive functioning.
Methods
Children (N = 206) participating in a longitudinal birth cohort study were assessed prospectively for exposure to IPT (physical or emotional abuse or neglect, sexual abuse, witnessing maternal partner violence) between birth and 64 months. Child intelligent quotient scores (IQ) were assessed at 24, 64, and 96 months of age. Race/ethnicity, gender, socioeconomic status, maternal IQ, birth complications, birthweight, and cognitive stimulation in the home were also assessed.
Results
IPT was significantly associated with decreased cognitive scores at all time points, even after controlling for sociodemographic factors, maternal IQ, birth complications, birthweight, and cognitive stimulation in the home. IPT in the first two years appeared to be especially detrimental. On average, compared to children not exposed to IPT in the first two years, exposed children scored one-half standard deviation lower across cognitive assessments.
Conclusion
IPT in early life may have adverse effects on cognitive development. IPT during the first two years may have particular impact, with effects persisting at least into later childhood.
doi:10.1136/jech-2011-200727
PMCID: PMC3731065  PMID: 22493459
cognitive development; IQ; trauma; child abuse; domestic violence
14.  Predictors of virtual radial arm maze performance in adolescent Italian children 
Neurotoxicology  2012;33(5):1203-1211.
Background
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.
Objective
To describe the characteristics and correlates of the Virtual Radial Arm Maze (VRAM) in 255 children age 10–15 years from Italy.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.neuro.2012.06.012
PMCID: PMC3470779  PMID: 22771383
Child behavior; computerized tests; environmental chemicals; epidemiology; toxicology
15.  Assessing windows of susceptibility to lead-induced cognitive deficits in Mexican children 
Neurotoxicology  2012;33(5):1040-1047.
Background
The identification of susceptible periods to Pb-induced decrements in childhood cognitive abilities remains elusive.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.neuro.2012.04.022
PMCID: PMC3576696  PMID: 22579785
Lead; Children; Epidemiology; Cognitive abilities; Windows of development
16.  The Outdoor Air Pollution and Brain Health Workshop 
Neurotoxicology  2012;33(5):972-984.
Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.
doi:10.1016/j.neuro.2012.08.014
PMCID: PMC3726250  PMID: 22981845
Air pollution; brain; particulate matter; ozone; central nervous system; susceptibility; epidemiology; neuroinflammation; neurotoxicity; behavior
17.  Urinary 8-Hydroxy-2′-Deoxyguanosine as a Biomarker of Oxidative DNA Damage Induced by Ambient Pollution in the Normative Aging Study 
Background
Studies show that exposure to air pollution damages human health, but the mechanisms are not fully understood. One suggested pathway is via oxidative stress.
Objectives
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.
Methods
We fit linear regression models to examine associations between air pollutants and 8-OHdG adjusting for potential confounders.
Results
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.
Conclusions
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.
doi:10.1136/oem.2010.056358
PMCID: PMC3786183  PMID: 20980452
8-Hydroxy-2′-Deoxyguanosine; air pollution; DNA damage; oxidative stress; biomarker
18.  Gene-Environment Interaction and Children’s Health and Development 
Current opinion in pediatrics  2010;22(2):197-201.
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.
Recent Findings
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.
Summary
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.
doi:10.1097/MOP.0b013e328336ebf9
PMCID: PMC2878613  PMID: 20090521
genetics; pediatrics; prenatal environment
19.  Arsenic exposure and DNA methylation among elderly men 
Epidemiology (Cambridge, Mass.)  2012;23(5):668-676.
BACKGROUND
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.
METHODS
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.
RESULTS
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]).
CONCLUSIONS
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.
doi:10.1097/EDE.0b013e31825afb0b
PMCID: PMC3448132  PMID: 22833016
20.  Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence and mortality in elderly individuals: the Normative Aging Study 
Cancer causes & control : CCC  2010;22(3):437-447.
Background
Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case-control studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case-control studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear.
Methods
In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing.
Results
Individuals with low LINE-1 methylation (
Conclusion
These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer.
doi:10.1007/s10552-010-9715-2
PMCID: PMC3752839  PMID: 21188491
Repetitive elements; DNA methylation; Epigenetics; Blood; Cancer risk
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.
doi:10.1530/JME-12-0066
PMCID: PMC3752847  PMID: 22798698
Epigenetics; DNA methylation; histone modifications; toxicology; endocrine disrupters
Current opinion in pediatrics  2011;23(2):227-232.
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 findings
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.
Summary
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.
doi:10.1097/MOP.0b013e328344568f
PMCID: PMC3753013  PMID: 21301340
preterm; disparities; environment; lead; air pollution
Pediatrics  2010;125(6):e1270-e1277.
Context
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.
Objective
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.
Results
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.
Conclusions
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.
doi:10.1542/peds.2009-3058
PMCID: PMC3706632  PMID: 20478945
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
Environmental Health Perspectives  2013;121(7):859-864.
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.
doi:10.1289/ehp.1205940
PMCID: PMC3701996  PMID: 23665743
attention; children; Conners’ Continuous Performance Test; hit reaction time; traffic-related air pollution; urban
Objective
We evaluated the modifying influence of a δ-aminolevulinic acid dehydratase (ALAD) polymorphism on the relation between lead burden and cognition among older men.
Methods
Information on ALAD genotype, lead measurements, potential confounders, and cognitive testing was collected from 982 participants. For each cognitive test and lead biomarker, we fit separate multiple linear regression models which included an interaction term for ALAD genotype and the lead biomarker, and adjusted for potential confounders.
Results
With higher levels of tibia lead, ALAD 1-2/2-2 carriers exhibited worse performance on a spatial copying test in comparison with ALAD 1-1 carriers (pinteraction=0.03). However, there was no consistent pattern of an ALAD genotype-lead interaction for the other tests.
Conclusions
The results provide some evidence that ALAD genotype modifies the relation between lead burden and cognition among older men with low lead burden, particularly for cognitive domains sensitive to the effects of cumulative lead burden.
doi:10.1097/JOM.0b013e3181792463
PMCID: PMC3664949  PMID: 18784554
blood; bone and blood; lead; environmental; polymorphism; genetic; cognition; neuropsychological tests

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