Associations of a toenail metal mixture with attention and memory in the Gulf long-term follow-up (GuLF) study.

BACKGROUND: Research on metal-associated neurodegeneration has largely focused on single metals. Since metal exposures typically co-occur as combinations of both toxic and essential elements, a mixtures framework is important for identifying risk and protective factors. This study examined associations between toenail levels of an eight-metal mixture and attention and memory in men living in US Gulf states. METHODS: We measured toenail concentrations of toxic (arsenic, chromium, lead, and mercury) and essential (copper, manganese, selenium, and zinc) metals in 413 non-smoking men (23-69 years, 46 % Black) from the Gulf Long-Term Follow-Up (GuLF) Study. Sustained attention and working memory were assessed at the time of toenail sample collection using the continuous performance test (CPT) and digit span test (DST), respectively. Associations between toenail metal concentrations and performance on neurobehavioral tests were characterized using co-pollutant adjusted general linear models and Bayesian Kernel Machine Regression. RESULTS: Adjusting for other metals, one interquartile range (IQR) increase in toenail chromium was associated with a 0.19 (95 % CI: -0.31, -0.07) point reduction in CPT D Prime score (poorer ability to discriminate test signals from noise). One IQR increase in toenail manganese was associated with a 0.20 (95 % CI, -0.41, 0.01) point reduction on the DST Reverse Count (fewer numbers recalled). Attention deficits were greater among Black participants compared to White participants for the same increase in toenail chromium concentrations. No evidence of synergistic interaction between metals or adverse effect of the overall metal mixture was observed for either outcome. CONCLUSIONS: Our findings support existing studies of manganese-related memory deficits and are some of the first to show chromium related attention deficits in adults. Longitudinal study of cognitive decline is needed to verify chromium findings. Research into social and chemical co-exposures is also needed to explain racial differences in metal-associated neurobehavioral deficits observed in this study.

Mixture of air pollution, brominated flame retardants, polychlorinated biphenyls, per- and polyfluoroalkyl substances, and organochlorine pesticides in relation to vitamin D concentrations in pregnancy.

Over two-thirds of pregnant women in the U.S. have insufficient 25(OH)D (Vitamin D) concentrations, which can adversely impact fetal health. Several pollutants have been associated with 25(OH)D, but have not been considered in the context of chemical co-exposures. We aimed to determine associations between a broad mixture of prenatal environmental chemical exposures and 25(OH)D concentrations in mid-pregnancy. Stored mid-pregnancy serum samples were assayed from 421 women delivering live births in Southern California in 2000-2003. 25(OH)D, six BFRs, eleven polychlorinated biphenyls (PCBs), six per- and polyfluoroalkyl substances, and two organochlorine pesticides were detected in ≥60% of specimens. Gestational exposures to airborne particulate matter ≤ 10 µm (PM10) and ≤ 2.5 µm (PM2.5), nitrogen monoxide (NO), nitrogen dioxide (NO2), and ozone concentrations were derived from monitoring station data. Bayesian Hierarchical Modeling (BHM) and Bayesian Kernel Machine Regression (BKMR) analyses estimated overall mixture and individual chemical associations accounting for co-exposures and covariates with mean 25(OH)D levels, and BHM was used to estimate associations with insufficient (<75 nMol/L) 25(OH)D levels. Non-mixture associations for each chemical were estimated with linear and logistic models. PM10 [BHM estimate: -0.133 nmol/l 95% Credible Interval (-0.240, -0.026)] was associated with lower 25(OH)D in BHM and BKMR. Higher quantiles of combined exposures were associated with lower 25(OH)D, though with wide credible intervals. In non-mixture models, PM10, PM2.5, NO, and NO2 were associated with lower concentrations, while O3 and PBDE153 were associated with higher 25(OH)D and/or lower insufficiency. While some chemicals were associated with increased and others with decreased 25(OH)D concentrations, the overall mixture was associated with lower concentrations. Mixture analyses differed from non-mixture regressions, highlighting the importance of mixtures approaches for estimating real-world associations.

Prenatal Exposure to Ambient Air Pollution and Epigenetic Aging at Birth in Newborns.

In utero air pollution exposure has been associated with adverse birth outcomes, yet effects of air pollutants on regulatory mechanisms in fetal growth and critical windows of vulnerability during pregnancy are not well understood. There is evidence that epigenetic alterations may contribute to these effects. DNA methylation (DNAm) based age estimators have been developed and studied extensively with health outcomes in recent years. Growing literature suggests environmental factors, such as air pollution and smoking, can influence epigenetic aging. However, little is known about the effect of prenatal air pollution exposure on epigenetic aging. In this study, we leveraged existing data on prenatal air pollution exposure and cord blood DNAm from 332 mother-child pairs in the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), two pregnancy cohorts enrolling women who had a previous child diagnosed with autism spectrum disorder, to assess the relationship of prenatal exposure to air pollution and epigenetic aging at birth. DNAm age was computed using existing epigenetic clock algorithms for cord blood tissue-Knight and Bohlin. Epigenetic age acceleration was defined as the residual of regressing chronological gestational age on DNAm age, accounting for cell type proportions. Multivariable linear regression models and distributed lag models (DLMs), adjusting for child sex, maternal race/ethnicity, study sites, year of birth, maternal education, were completed. In the single-pollutant analysis, we observed exposure to PM2.5, PM10, and O3 during preconception period and pregnancy period were associated with decelerated epigenetic aging at birth. For example, pregnancy average PM10 exposure (per 10 unit increase) was associated with epigenetic age deceleration at birth (weeks) for both Knight and Bohlin clocks (ß = -0.62, 95% CI: -1.17, -0.06; ß = -0.32, 95% CI: -0.63, -0.01, respectively). Weekly DLMs revealed that increasing PM2.5 during the first trimester and second trimester were associated with decelerated epigenetic aging and that increasing PM10 during the preconception period was associated with decelerated epigenetic aging, using the Bohlin clock estimate. Prenatal ambient air pollution exposure, particularly in early and mid-pregnancy, was associated with decelerated epigenetic aging at birth.

Pre- and Postnatal Fine Particulate Matter Exposure and Childhood Cognitive and Adaptive Function.

Increasing evidence exists for an association between early life fine particulate matter (PM2.5) exposure and several neurodevelopmental outcomes, including autism spectrum disorder (ASD); however, the association between PM2.5 and adaptive and cognitive function remains poorly understood. Participants included 658 children with ASD, 771 with a non-ASD developmental disorder, and 849 population controls from the Study to Explore Early Development. Adaptive functioning was assessed in ASD cases using the Vineland Adaptive Behavior Scales (VABS); cognitive functioning was assessed in all groups using the Mullen Scales of Early Learning (MSEL). A satellite-based model was used to assign PM2.5 exposure averages during pregnancy, each trimester, and the first year of life. Linear regression was used to estimate beta coefficients and 95% confidence intervals, adjusting for maternal age, education, prenatal tobacco use, race-ethnicity, study site, and season of birth. PM2.5 exposure was associated with poorer VABS scores for several domains, including daily living skills and socialization. Associations were present between prenatal PM2.5 and lower MSEL scores for all groups combined; results were most prominent for population controls in stratified analyses. These data suggest that early life PM2.5 exposure is associated with specific aspects of cognitive and adaptive functioning in children with and without ASD.

The association of unconventional natural gas development with diagnosis and treatment of internalizing disorders among adolescents in Pennsylvania using electronic health records.

BACKGROUND: Unconventional natural gas development (UNGD) introduces physical and psychosocial hazards into communities, which could contribute to psychosocial stress in adolescents and an increased risk of internalizing disorders, common and impactful health outcomes. OBJECTIVES: To evaluate associations between a 180-day composite UNGD activity metric and new onset of internalizing disorders, overall and separately for anxiety and depressive disorders, and effect modification by sex. METHODS: We used a nested case-control design from 2008 to 2016 in 38 Pennsylvania counties using electronic health records from adolescent Geisinger subjects. Cases were defined by at least two diagnoses or medication orders indicating new onset of an internalizing disorder, and controls frequency-matched 4:1 on age, sex, and year. To evaluate associations, we used generalized estimating equations, with logit link, robust standard errors, and an exchangeable correlation structure within community. RESULTS: We identified 7,974 adolescents (65.9% female, mean age 15.0 years) with new onset internalizing disorders. There were no associations when we used data from the entire study period. When restricted to years with higher UNGD activity (2010-2016), comparing the highest to lowest quartile, UNGD activity was associated (odds ratio [95% confidence level]) with new onset internalizing disorders (1.15 [1.06, 1.25]). Associations were slightly stronger for depressive disorders. Associations were only present in females (p = 0.009). DISCUSSION: This is the first epidemiologic study of UNGD in relation to adolescent mental health, an important health outcome in a potentially susceptible group to the environmental and community impacts of UNGD. UNGD activity was associated with new onset internalizing disorders in females in this large sample in an area of active UNGD.

Maternal tobacco smoking and offspring autism spectrum disorder or traits in ECHO cohorts.

Given inconsistent evidence on preconception or prenatal tobacco use and offspring autism spectrum disorder (ASD), this study assessed associations of maternal smoking with ASD and ASD-related traits. Among 72 cohorts in the Environmental Influences on Child Health Outcomes consortium, 11 had ASD diagnosis and prenatal tobaccosmoking (n = 8648). and 7 had Social Responsiveness Scale (SRS) scores of ASD traits (n = 2399). Cohorts had diagnoses alone (6), traits alone (2), or both (5). Diagnoses drew from parent/caregiver report, review of records, or standardized instruments. Regression models estimated smoking-related odds ratios (ORs) for diagnoses and standardized mean differences for SRS scores. Cohort-specific ORs were meta-analyzed. Overall, maternal smoking was unassociated with child ASD (adjusted OR, 1.08; 95% confidence interval [CI], 0.72-1.61). However, heterogeneity across studies was strong: preterm cohorts showed reduced ASD risk for exposed children. After excluding preterm cohorts (biased by restrictions on causal intermediate and exposure opportunity) and small cohorts (very few ASD cases in either smoking category), the adjusted OR for ASD from maternal smoking was 1.44 (95% CI, 1.02-2.03). Children of smoking (versus non-smoking) mothers had more ASD traits (SRS T-score + 2.37 points, 95% CI, 0.73-4.01 points), with results homogeneous across cohorts. Maternal preconception/prenatal smoking was consistently associated with quantitative ASD traits and modestly associated with ASD diagnosis among sufficiently powered United States cohorts of non-preterm children. Limitations resulting from self-reported smoking and unmeasured confounders preclude definitive conclusions. Nevertheless, counseling on potential and known risks to the child from maternal smoking is warranted for pregnant women and pregnancy planners. LAY SUMMARY: Evidence on the association between maternal prenatal smoking and the child's risk for autism spectrum disorder has been conflicting, with some studies reporting harmful effects, and others finding reduced risks. Our analysis of children in the ECHO consortium found that maternal prenatal tobacco smoking is consistently associated with an increase in autism-related symptoms in the general population and modestly associated with elevated risk for a diagnosis of autism spectrum disorder when looking at a combined analysis from multiple studies that each included both pre- and full-term births. However, this study is not proof of a causal connection. Future studies to clarify the role of smoking in autism-like behaviors or autism diagnoses should collect more reliable data on smoking and measure other exposures or lifestyle factors that might have confounded our results.

Maternal blood metal concentrations and whole blood DNA methylation during pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI).

The maternal epigenome may be responsive to prenatal metals exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation. In the Early Autism Risk Longitudinal Investigation cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured on the Illumina 450 K array. A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal. We observed hypermethylation at 11 DNA methylation sites associated with lead (FDR False Discovery Rate q-value <0.1), near the genes CYP24A1, ASCL2, FAT1, SNX31, NKX6-2, LRC4C, BMP7, HOXC11, PCDH7, ZSCAN18, and VIPR2. Lead-associated sites were enriched (FDR q-value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR q-value <0.1), one of which was near the gene ARID2. Manganese-associated sites were enriched for cellular metabolism pathways (FDR q-value<0.1). Effect estimates for DNA methylation sites associated (p < 0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ > 0.86). DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways.

Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene.

BACKGROUND: Independent studies report association of autism spectrum disorder with air pollution exposure and a functional promoter variant (rs1858830) in the MET receptor tyrosine kinase (MET) gene. Toxicological data find altered brain Met expression in mice after prenatal exposure to a model air pollutant. Our objective was to investigate whether air pollution exposure and MET rs1858830 genotype interact to alter the risk of autism spectrum disorder. METHODS: We studied 252 cases of autism spectrum disorder and 156 typically developing controls from the Childhood Autism Risk from Genetics and the Environment Study. Air pollution exposure was assigned for local traffic-related sources and regional sources (particulate matter, nitrogen dioxide, and ozone). MET genotype was determined by direct resequencing. RESULTS: Subjects with both MET rs1858830 CC genotype and high air pollutant exposures were at increased risk of autism spectrum disorder compared with subjects who had both the CG/GG genotypes and lower air pollutant exposures. There was evidence of multiplicative interaction between NO2 and MET CC genotype (P= 0.03). CONCLUSIONS: MET rs1858830 CC genotype and air pollutant exposure may interact to increase the risk of autism spectrum disorder.

Residential proximity to freeways and autism in the CHARGE study.

BACKGROUND: Little is known about environmental causes and contributing factors for autism. Basic science and epidemiologic research suggest that oxidative stress and inflammation may play a role in disease development. Traffic-related air pollution, a common exposure with established effects on these pathways, contains substances found to have adverse prenatal effects. OBJECTIVES: We examined the association between autism and proximity of residence to freeways and major roadways during pregnancy and near the time of delivery, as a surrogate for air pollution exposure. METHODS: Data were from 304 autism cases and 259 typically developing controls enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) study. The mother's address recorded on the birth certificate and trimester-specific addresses derived from a residential history obtained by questionnaire were geocoded, and measures of distance to freeways and major roads were calculated using ArcGIS software. Logistic regression models compared residential proximity to freeways and major roads for autism cases and typically developing controls. RESULTS: Adjusting for sociodemographic factors and maternal smoking, maternal residence at the time of delivery was more likely be near a freeway (≤ 309 m) for cases than for controls [odds ratio (OR)=1.86; 95% confidence interval (CI), 1.04-3.45]. Autism was also associated with residential proximity to a freeway during the third trimester (OR=2.22; CI, 1.16-4.42). After adjustment for socioeconomic and sociodemographic characteristics, these associations were unchanged. Living near other major roads at birth was not associated with autism. CONCLUSIONS: Living near a freeway was associated with autism. Examination of associations with measured air pollutants is needed.

Evidence for specificity of transmission of alcohol and nicotine dependence in an offspring of twins design.

Alcohol dependence (AD) and nicotine dependence (ND) have been shown to co-occur. Results from twin studies implicate the role of genetics in the etiology of both ND and AD with substantial, yet incomplete, overlap. To test for specificity of transmission of AD and ND in an offspring of twins sample we analyzed data from a study of adolescent and adult offspring of twin fathers ascertained from the Vietnam Era Twin Registry. This sample consists of 1213 twin fathers, 862 biologic or rearing mothers, and 1270 offspring. Offspring were allocated to one of four risk groups for AD based on twin fathers' zygosity and father's and cotwins AD history. Offspring DSM-IV AD and ND were measured by structured diagnostic interview. Paternal AD and ND were significantly associated with offspring AD and ND, respectively. Bivariate probit regression results suggest specificity for transmission of AD and ND. This remained constant after controlling for offspring demographics and psychopathology and maternal AD and ND. Despite the substantial genetic overlap between the two disorders, there is evidence for genetic effects specific for AD and ND.