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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  Environmental Epigenetics: A Role in Endocrine Disease? 
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
13.  Racial/ethnic disparities in preterm birth: clues from environmental exposures 
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
14.  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
15.  ATTENTION DEFICIT/HYPERACTIVITY DISORDER AND URINARY METABOLITES OF ORGANOPHOSPHATE PESTICIDES IN U.S. CHILDREN 8–15 YEARS 
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
16.  Associations between Traffic-Related Black Carbon Exposure and Attention in a Prospective Birth Cohort of Urban Children 
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
17.  Dysregulation of BDNF-TrkB Signaling in Developing Hippocampal Neurons by Pb2+: Implications for an Environmental Basis of Neurodevelopmental Disorders 
Toxicological Sciences  2012;127(1):277-295.
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.
doi:10.1093/toxsci/kfs090
PMCID: PMC3327871  PMID: 22345308
BDNF; TrkB; p75NTR; MeCP2; epigenetics; Huntingtin; Synapsin I; phosphorylation; Pb2+; hippocampus; neuron; synaptogenesis
18.  Neurotoxicology: What can context teach us? 
The Journal of pediatrics  2008;152(2):155-157.
doi:10.1016/j.jpeds.2007.10.040
PMCID: PMC2243177  PMID: 18206679
19.  Modification by hemochromatosis gene polymorphisms of the association between traffic-related air pollution and cognition in older men: a cohort study 
Environmental Health  2013;12:16.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1476-069X-12-16
PMCID: PMC3599892  PMID: 23413885
Aging; Black carbon; Cognitive dysfunction; Epidemiology; Particulate matter; HFE; Hemochromatosis; Gene-environment interaction; Susceptible group
20.  Associations between cadmium exposure and neurocognitive test scores in a cross-sectional study of US adults 
Environmental Health  2013;12:13.
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1476-069X-12-13
PMCID: PMC3599125  PMID: 23379984
Cadmium; Neurocognitive; Neuropsychological; NES2; NHANES; Attention; Smoking; Metals; Aging; Cognitive
21.  Design and analysis issues in gene and environment studies 
Environmental Health  2012;11:93.
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.
doi:10.1186/1476-069X-11-93
PMCID: PMC3551668  PMID: 23253229
Gene-environment; Interactions; Expanded environmental genomic disease paradigm; Critical developmental windows; Genome-wide; Epigenetics
22.  Childhood and Adult Socioeconomic Position, Cumulative Lead Levels, and Pessimism in Later Life 
American Journal of Epidemiology  2011;174(12):1345-1353.
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.
doi:10.1093/aje/kwr269
PMCID: PMC3276297  PMID: 22071587
depression; lead; metals; orientation; psychology; socioeconomic factors
23.  A dopamine receptor (DRD2) but not dopamine transporter (DAT1) gene polymorphism is associated with neurocognitive development of Mexican preschool children with lead exposure 
The Journal of pediatrics  2011;159(4):638-643.
Objective
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.
Study design
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.
Results
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.
Conclusion
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.
doi:10.1016/j.jpeds.2011.03.043
PMCID: PMC3158955  PMID: 21592505
Cord blood lead; postnatal lead exposure; DAT1; DRD2; gene polymorphisms; Mexico; child development
24.  Metal sources and exposures in the homes of young children living near a mining-impacted Superfund site 
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.
doi:10.1038/jes.2011.21
PMCID: PMC3161168  PMID: 21587306
house dust; indoor air pollution; metals; mine waste; residential exposures; Tar Creek Superfund Site
25.  Blood lead levels and cumulative blood lead index (CBLI) as predictors of late neurodevelopment in lead poisoned children 
Objective
To find the best lead exposure assessment marker for children.
Methods
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.
Results
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.
Conclusion
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.
doi:10.3109/1354750X.2011.604133
PMCID: PMC3229913  PMID: 21827276
Heavy metal toxicity; neurological disease; environmental pollution/ecotoxicology

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