The association between neighborhood deprivation and DNA methylation in an autopsy cohort.

Previous research has found that living in a disadvantaged neighborhood is associated with poor health outcomes. Living in disadvantaged neighborhoods may alter inflammation and immune response in the body, which could be reflected in epigenetic mechanisms such as DNA methylation (DNAm). We used robust linear regression models to conduct an epigenome-wide association study examining the association between neighborhood deprivation (Area Deprivation Index; ADI), and DNAm in brain tissue from 159 donors enrolled in the Emory Goizueta Alzheimer's Disease Research Center (Georgia, USA). We found one CpG site (cg26514961, gene PLXNC1) significantly associated with ADI after controlling for covariates and multiple testing (p-value=5.0e-8). Effect modification by APOE ε4 was statistically significant for the top ten CpG sites from the EWAS of ADI, indicating that the observed associations between ADI and DNAm were mainly driven by donors who carried at least one APOE ε4 allele. Four of the top ten CpG sites showed a significant concordance between brain tissue and tissues that are easily accessible in living individuals (blood, buccal cells, saliva), including DNAm in cg26514961 (PLXNC1). Our study identified one CpG site (cg26514961, PLXNC1 gene) that was significantly associated with neighborhood deprivation in brain tissue. PLXNC1 is related to immune response, which may be one biological pathway how neighborhood conditions affect health. The concordance between brain and other tissues for our top CpG sites could make them potential candidates for biomarkers in living individuals.

Joint effects of prenatal exposure to indoor air pollution and psychosocial factors on early life inflammation.

It is hypothesized that air pollution and stress impact the central nervous system through neuroinflammatory pathways Despite this, the association between prenatal exposure to indoor air pollution and psychosocial factors on inflammatory markers in infancy has been underexplored in epidemiology studies. This study investigates the individual and joint effects of prenatal exposure to indoor air pollution and psychosocial factors on early life inflammation (interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)). We analyzed data from the South African Drakenstein Child Health Study (N = 225). Indoor air pollution and psychosocial factor measurements were taken in the 2nd trimester of pregnancy. Circulating inflammatory markers (IL-1ß, Il-6, and TNF-α) were measured in serum in the infants at 6 weeks postnatal. Linear regression models were used to investigate associations between individual exposures and inflammatory markers. To investigate joint effects of environmental and psychosocial factors, Self-Organizing Maps (SOM) were used to create exposure profile clusters. These clusters were added to linear regression models to investigate the associations between exposure profiles and inflammatory markers. All models were adjusted for maternal age, maternal HIV status, and ancestry to control for confounding. Most indoor air pollutants were positively associated with inflammatory markers, particularly benzene and TNF-α in single pollutant models. No consistent patterns were found for psychosocial factors in single-exposure linear regression models. In joint effects analyses, the SOM profile with high indoor air pollution, low SES, and high maternal depressive symptoms were associated with higher inflammation. Indoor air pollutants were consistently associated with increased inflammation in both individual and joint effects models, particularly in combination with low SES and maternal depressive symptoms. The trend for individual psychosocial factors was not as clear, with mainly null associations. As we have observed pro- and anti-inflammatory effects, future research should investigate joint effects of these exposures on inflammation and their health effects.

Association between Fine Particulate Matter Exposure and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease among a Cognitively Healthy Population-Based Cohort.

BACKGROUND: Epidemiological evidence suggests air pollution adversely affects cognition and increases the risk of Alzheimer's disease (AD), but little is known about the biological effects of fine particulate matter (PM2.5, particulate matter with aerodynamic diameter ≤2.5µm) on early predictors of future disease risk. OBJECTIVES: We investigated the association between 1-, 3-, and 5-y exposure to ambient and traffic-related PM2.5 and cerebrospinal fluid (CSF) biomarkers of AD. METHODS: We conducted a cross-sectional analysis using data from 1,113 cognitively healthy adults (45-75 y of age) from the Emory Healthy Brain Study in Georgia in the United States. CSF biomarker concentrations of Aß42, tTau, and pTau, were collected at enrollment (2016-2020) and analyzed with the Roche Elecsys system. Annual ambient and traffic-related residential PM2.5 concentrations were estimated at a 1-km and 250-m resolution, respectively, and computed for each participant's geocoded address, using three exposure time periods based on specimen collection date. Associations between PM2.5 and CSF biomarker concentrations, considering continuous and dichotomous (dichotomized at clinical cutoffs) outcomes, were estimated with multiple linear/logistic regression, respectively, controlling for potential confounders (age, gender, race, ethnicity, body mass index, and neighborhood socioeconomic status). RESULTS: Interquartile range (IQR; IQR=0.845) increases in 1-y [ß:-0.101; 95% confidence interval (CI): -0.18, -0.02] and 3-y (ß:-0.078; 95% CI: -0.15, -0.00) ambient PM2.5 exposures were negatively associated with Aß42 CSF concentrations. Associations between ambient PM2.5 and Aß42 were similar for 5-y estimates (ß:-0.076; 95% CI: -0.160, 0.005). Dichotomized CSF variables revealed similar associations between ambient PM2.5 and Aß42. Associations with traffic-related PM2.5 were similar but not significant. Associations between PM2.5 exposures and tTau, pTau tTau/Aß42, or pTau/Aß42 levels were mainly null. CONCLUSION: In our study, consistent trends were found between 1-y PM2.5 exposure and decreased CSF Aß42, which suggests an accumulation of amyloid plaques in the brain and an increased risk of developing AD. https://doi.org/10.1289/EHP13503.

Joint Effects of Indoor Air Pollution and Maternal Psychosocial Factors During Pregnancy on Trajectories of Early Childhood Psychopathology.

BACKGROUND: Prenatal indoor air pollution and maternal psychosocial factors have been associated with adverse psychopathology. We used environmental exposure mixture methodology to investigate joint effects of both exposure classes on child behavior trajectories. METHODS: For 360 children from the South African Drakenstein Child Health Study, we created trajectories of Child Behavior Checklist scores (24, 42, 60 months) using latent class linear mixed effects models. Indoor air pollutants and psychosocial factors were measured during pregnancy (2nd trimester). After adjusting for confounding, single-exposure effects (per natural log-1 unit increase) were assessed using polytomous logistic regression models; joint effects using self-organizing maps (SOM), and principal component (PC) analysis. RESULTS: Three trajectories were chosen for both internalizing and externalizing problems, with "high" (externalizing) or "increasing" (internalizing) being the most adverse trajectories. High externalizing trajectory was associated with increased particulate matter (PM10) exposure (OR [95%-CI]: 1.25 [1.01,1.55]) and SOM exposure profile most associated with smoking (2.67 [1.14,6.27]). Medium internalizing trajectory was associated with increased emotional intimate partner violence (2.66 [1.17,5.57]), increasing trajectory with increased benzene (1.24 [1.02,1.51]) and toluene (1.21 [1.02,1.44]) and the PC most correlated with benzene and toluene (1.25 [1.02, 1.54]). CONCLUSIONS: Prenatal exposure to environmental pollutants and psychosocial factors was associated with internalizing and externalizing child behavior trajectories. Understanding joint effects of adverse exposure mixtures will facilitate targeted interventions to prevent childhood psychopathology.

Joint effects of air pollution and neighborhood socioeconomic status on cognitive decline - Mediation by depression, high cholesterol levels, and high blood pressure.

Air pollution and neighborhood socioeconomic status (N-SES) are associated with adverse cardiovascular health and neuropsychiatric functioning in older adults. This study examines the degree to which the joint effects of air pollution and N-SES on the cognitive decline are mediated by high cholesterol levels, high blood pressure (HBP), and depression. In the Emory Healthy Aging Study, 14,390 participants aged 50+ years from Metro Atlanta, GA, were assessed for subjective cognitive decline using the cognitive function instrument (CFI). Information on the prior diagnosis of high cholesterol, HBP, and depression was collected through the Health History Questionnaire. Participants' census tracts were assigned 3-year average concentrations of 12 air pollutants and 16 N-SES characteristics. We used the unsupervised clustering algorithm Self-Organizing Maps (SOM) to create 6 exposure clusters based on the joint distribution of air pollution and N-SES in each census tract. Linear regression analysis was used to estimate the effects of the SOM cluster indicator on CFI, adjusting for age, race/ethnicity, education, and neighborhood residential stability. The proportion of the association mediated by high cholesterol levels, HBP, and depression was calculated by comparing the total and direct effects of SOM clusters on CFI. Depression mediated up to 87 % of the association between SOM clusters and CFI. For example, participants living in the high N-SES and high air pollution cluster had CFI scores 0.05 (95 %-CI:0.01,0.09) points higher on average compared to those from the high N-SES and low air pollution cluster; after adjusting for depression, this association was attenuated to 0.01 (95 %-CI:-0.04,0.05). HBP mediated up to 8 % of the association between SOM clusters and CFI and high cholesterol up to 5 %. Air pollution and N-SES associated cognitive decline was partially mediated by depression. Only a small portion (<10 %) of the association was mediated by HBP and high cholesterol.

Differential DNA methylation in the brain as potential mediator of the association between traffic-related PM2.5 and neuropathology markers of Alzheimer's disease.

INTRODUCTION: Growing evidence indicates that fine particulate matter (PM2.5) is a risk factor for Alzheimer's disease (AD), but the underlying mechanisms have been insufficiently investigated. We hypothesized differential DNA methylation (DNAm) in brain tissue as a potential mediator of this association. METHODS: We assessed genome-wide DNAm (Illumina EPIC BeadChips) in prefrontal cortex tissue and three AD-related neuropathological markers (Braak stage, CERAD, ABC score) for 159 donors, and estimated donors' residential traffic-related PM2.5 exposure 1, 3, and 5 years prior to death. We used a combination of the Meet-in-the-Middle approach, high-dimensional mediation analysis, and causal mediation analysis to identify potential mediating CpGs. RESULTS: PM2.5 was significantly associated with differential DNAm at cg25433380 and cg10495669. Twenty-four CpG sites were identified as mediators of the association between PM2.5 exposure and neuropathology markers, several located in genes related to neuroinflammation. DISCUSSION: Our findings suggest differential DNAm related to neuroinflammation mediates the association between traffic-related PM2.5 and AD. HIGHLIGHTS: First study to evaluate the potential mediation effect of DNA methylation for the association between PM2.5 exposure and neuropathological changes of Alzheimer's disease. Study was based on brain tissues rarely investigated in previous air pollution research. Cg10495669, assigned to RBCK1 gene playing a role in inflammation, was associated consistently with 1-year, 3-year, and 5-year traffic-related PM2.5 exposures prior to death. Meet-in-the-middle approach and high-dimensional mediation analysis were used simultaneously to increase the potential of identifying the differentially methylated CpGs. Differential DNAm related to neuroinflammation was found to mediate the association between traffic-related PM2.5 and Alzheimer's disease.

Contributions of prenatal risk factors and neonatal epigenetics to cognitive outcome in children born very preterm.

Children born less than 30 weeks gestational age (GA) are at high risk for neurodevelopmental delay compared to term peers. Prenatal risk factors and neonatal epigenetics could help identify preterm children at highest risk for poor cognitive outcomes. We aimed to understand the associations among cumulative prenatal risk, neonatal DNA methylation, and child cognitive ability at age 3 years, including whether DNA methylation mediates the association between prenatal risk and cognitive ability. We studied 379 neonates (54% male) born less than 30 weeks GA who had DNA methylation measured at neonatal intensive care unit discharge along with 3-year follow-up data. Cumulative prenatal risk was calculated from 24 risk factors obtained from maternal report and medical record and epigenome-wide neonatal DNA methylation was assayed from buccal swabs. At 3-year follow-up, child cognitive ability was assessed using the Bayley Scales of Infant and Toddler Development (third edition). Cumulative prenatal risk and DNA methylation at two cytosine-phosphate-guanines (CpGs) were uniquely associated with child cognitive ability. Using high-dimensional mediation analysis, we also identified differential methylation of 309 CpGs that mediated the association between cumulative prenatal risk and child cognitive ability. Many of the associated CpGs were located in genes (TNS3, TRAPPC4, MAD1L1, APBB2, DIP2C, TRAPPC9, DRD2) that have previously been associated with prenatal exposures and/or neurodevelopmental phenotypes. Our findings suggest a role for both prenatal risk factors and DNA methylation in explaining outcomes for children born preterm and suggest we should further study DNA methylation as a potential mechanism underlying the association between prenatal risk and child neurodevelopment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Association of PM2.5 Exposure and Alzheimer Disease Pathology in Brain Bank Donors-Effect Modification by APOE Genotype.

BACKGROUND AND OBJECTIVES: Fine particulate matter (PM2.5) exposure has been found to be associated with Alzheimer disease (AD) and is hypothesized to cause inflammation and oxidative stress in the brain, contributing to neuropathology. The APOE gene, a major genetic risk factor of AD, has been hypothesized to modify the association between PM2.5 and AD. However, little prior research exists to support these hypotheses. This study investigates the association between traffic-related PM2.5 and AD hallmark pathology, including effect modification by APOE genotype, in an autopsy cohort. METHODS: A cross-sectional study was conducted using brain tissue donors enrolled in the Emory Goizueta AD Research Center who died before 2020 (n = 224). Donors were assessed for AD pathology including the Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC) score. Traffic-related PM2.5 concentrations were modeled for the metro-Atlanta area during 2002-2019 with a spatial resolution of 200-250 m. One-year, 3-year, and 5-year average PM2.5 concentrations before death were matched to participants' home address. We assessed the association between traffic-related PM2.5 and AD hallmark pathology and effect modification by APOE genotype, using adjusted ordinal logistic regression models. RESULTS: Among the 224 participants, the mean age of death was 76 years, and 57% had at least 1 APOE ε4 copy. Traffic-related PM2.5 was significantly associated with the CERAD score for the 1-year exposure window (odds ratio [OR] 1.92; 95% CI 1.12-3.30) and the 3-year exposure window (OR 1.87; 95% CI 1.01-3.17). PM2.5 was also associated with higher Braak stage and ABC score albeit nonsignificantly. The strongest associations between PM2.5 and neuropathology markers were among those without APOE ε4 alleles (e.g., for the CERAD score and 1-year exposure window, OR 2.31; 95% CI 1.36-3.94), though interaction between PM2.5 and APOE genotype was not statistically significant. DISCUSSION: Our study found traffic-related PM2.5 exposure was associated with the CERAD score in an autopsy cohort, contributing to epidemiologic evidence that PM2.5 affects ß-amyloid deposition in the brain. This association was particularly strong among donors without APOE ε4 alleles. Future studies should further investigate the biological mechanisms behind this association.

Sensitive periods for exposure to indoor air pollutants and psychosocial factors in association with symptoms of psychopathology at school-age in a South African birth cohort.

Background: Gestation and the first few months of life are important periods for brain development. During these periods, exposure to environmental toxicants and psychosocial stressors are particularly harmful and may impact brain development. Specifically, exposure to indoor air pollutants (IAP) and psychosocial factors (PF) during these sensitive periods has been shown to predict childhood psychopathology. Objectives: This study aims to investigate sensitive periods for the individual and joint effects of IAP and PF on childhood psychopathology at 6.5 years. Methods: We analyzed data from the Drakenstein Child Health Study (N=599), a South African birth cohort. Exposure to IAP and PF was measured during the second trimester of pregnancy and 4 months postpartum. The outcome of childhood psychopathology was assessed at 6.5 years old using the Childhood Behavior Checklist (CBCL). We investigated individual effects of either pre-or postnatal exposure to IAP and PF on CBCL scores using adjusted linear regression models, and joint effects of these exposures using quantile g-computation and self-organizing maps (SOM). To identify possible sensitive periods, we used a structured life course modeling approach (SLCMA) as well as exposure mixture methods (quantile g-computation and SOM). Results: Prenatal exposure to IAP or PFs, as well as the total prenatal mixture assessed using quantile g-computation, were associated with increased psychopathology. SLCMA and SOM models also indicated that the prenatal period is a sensitive period for IAP exposure on childhood psychopathology. Depression and alcohol were associated in both the pre-and postnatal period, while CO was associated with the postnatal period. Discussion: Pregnancy may be a sensitive period for the effect of indoor air pollution on childhood psychopathology. Exposure to maternal depression and alcohol in both periods was also associated with psychopathology. Determining sensitive periods of exposure is vital to ensure effective interventions to reduce childhood psychopathology.

Environmental, social and behavioral risk factors in association with spatial clustering of childhood cancer incidence.

Childhood cancer incidence is known to vary by age, sex, and race/ethnicity, but evidence is limited regarding external risk factors. We aim to identify harmful combinations of air pollutants and other environmental and social risk factors in association with the incidence of childhood cancer based on 2003-2017 data from the Georgia Cancer Registry. We calculated the standardized incidence ratios (SIR) of Central Nervous System (CNS) tumors, leukemia and lymphomas based on age, gender and ethnic composition in each of the 159 counties in Georgia, USA. County-level information on air pollution, socioeconomic status (SES), tobacco smoking, alcohol drinking and obesity were derived from US EPA and other public data sources. We applied two unsupervised learning tools (self-organizing map [SOM] and exposure-continuum mapping [ECM]) to identify pertinent types of multi-exposure combinations. Spatial Bayesian Poisson models (Leroux-CAR) were fit with indicators for each multi-exposure category as exposure and SIR of childhood cancers as outcomes. We identified consistent associations of environmental (pesticide exposure) and social/behavioral stressors (low socioeconomic status, alcohol) with spatial clustering of pediatric cancer class II (lymphomas and reticuloendothelial neoplasms), but not for other cancer classes. More research is needed to identify the causal risk factors for these associations.

Joint Effects of Indoor Air Pollution and Maternal Psychosocial Factors During Pregnancy on Trajectories of Early Childhood Psychopathology.

Background: Prenatal indoor air pollution and maternal psychosocial factors have been associated with adverse psychopathology. We used environmental exposure mixture methodology to investigate joint effects of both exposure classes on child behavior trajectories. Methods: For 360 children from the South African Drakenstein Child Health Study, we created trajectories of Child Behavior Checklist scores (24, 42, 60 months) using latent class linear mixed effects models. Indoor air pollutants and psychosocial factors were measured during pregnancy (2 nd trimester). After adjusting for confounding, single-exposure effects (per natural log-1 unit increase) were assessed using polytomous logistic regression models; joint effects using self-organizing maps (SOM), and principal component (PC) analysis. Results: High externalizing trajectory was associated with increased particulate matter (PM 10 ) exposure (OR [95%-CI]: 1.25 [1.01,1.55]) and SOM exposure profile most associated with smoking (2.67 [1.14,6.27]). Medium internalizing trajectory was associated with increased emotional intimate partner violence (2.66 [1.17,5.57]), increasing trajectory with increased benzene (1.24 [1.02,1.51]) and toluene (1.21 [1.02,1.44]) and the PC most correlated with benzene and toluene (1.25 [1.02, 1.54]). Conclusions: Prenatal exposure to environmental pollutants and psychosocial factors was associated with internalizing and externalizing child behavior trajectories. Understanding joint effects of adverse exposure mixtures will facilitate targeted interventions to prevent childhood psychopathology.

Pruning and thresholding approach for methylation risk scores in multi-ancestry populations.

Recent efforts have focused on developing methylation risk scores (MRS), a weighted sum of the individual's DNA methylation (DNAm) values of pre-selected CpG sites. Most of the current MRS approaches that utilize Epigenome-wide association studies (EWAS) summary statistics only include genome-wide significant CpG sites and do not consider co-methylation. New methods that relax the p-value threshold to include more CpG sites and account for the inter-correlation of DNAm might improve the predictive performance of MRS. We paired informed co-methylation pruning with P-value thresholding to generate pruning and thresholding (P+T) MRS and evaluated its performance among multi-ancestry populations. Through simulation studies and real data analyses, we demonstrated that pruning provides an improvement over simple thresholding methods for prediction of phenotypes. We demonstrated that European-derived summary statistics can be used to develop P+T MRS among other populations such as African populations. However, the prediction accuracy of P+T MRS may differ across multi-ancestry population due to environmental/cultural/social differences.

DNA methylation as a potential mediator of the association between indoor air pollution and neurodevelopmental delay in a South African birth cohort.

BACKGROUND: Exposure to indoor air pollution during pregnancy has been linked to neurodevelopmental delay in toddlers. Epigenetic modification, particularly DNA methylation (DNAm), may explain this link. In this study, we employed three high-dimensional mediation analysis methods (HIMA, DACT, and gHMA) followed by causal mediation analysis to identify differentially methylated CpG sites and genes that mediate the association between indoor air pollution and neurodevelopmental delay. Analyses were performed using data from 142 mother to child pairs from a South African birth cohort, the Drakenstein Child Health Study. DNAm from cord blood was measured using the Infinium MethylationEPIC and HumanMethylation450 arrays. Neurodevelopment was assessed at age 2 years using the Bayley Scores of Infant and Toddler Development, 3rd edition across four domains (cognitive development, general adaptive behavior, language, and motor function). Particulate matter with an aerodynamic diameter of 10 µm or less (PM10) was measured inside participants' homes during the second trimester of pregnancy. RESULTS: A total of 29 CpG sites and 4 genes (GOPC, RP11-74K11.1, DYRK1A, RNMT) were identified as significant mediators of the association between PM10 and cognitive neurodevelopment. The estimated proportion mediated (95%-confidence interval) ranged from 0.29 [0.01, 0.86] for cg00694520 to 0.54 [0.11, 1.56] for cg05023582. CONCLUSIONS: Our findings suggest that DNAm may mediate the association between prenatal PM10 exposure and cognitive neurodevelopment. DYRK1A and several genes that our CpG sites mapped to, including CNKSR1, IPO13, IFNGR1, LONP2, and CDH1, are associated with biological pathways implicated in cognitive neurodevelopment and three of our identified CpG sites (cg23560546 [DAPL1], cg22572779 [C6orf218], cg15000966 [NT5C]) have been previously associated with fetal brain development. These findings are novel and add to the limited literature investigating the relationship between indoor air pollution, DNAm, and neurodevelopment, particularly in low- and middle-income country settings and non-white populations.

Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.

Prenatal exposure to persistent and non-persistent chemical mixtures and associations with adverse birth outcomes in the Atlanta African American Maternal-Child Cohort.

BACKGROUND: African Americans (AAs) experience higher rates of preterm birth and fetal growth restriction relative to other pregnant populations. Differential in utero exposure to environmental chemicals may partially explain these health disparities, as AAs are disproportionately exposed to environmental hazards. OBJECTIVE: We examined the individual and mixture effects of non-persistent chemicals and persistent organic pollutants (POPs) on gestational age at birth and birthweight for gestational age z-scores within a prospective cohort of pregnant AAs. METHODS: First-trimester serum and urine samples obtained from participants within the Atlanta African American Maternal-Child cohort were analyzed for 43 environmental chemicals, including per-and polyfluoroalkyl substances (PFAS), polybrominated diphenyl ethers (PBDEs), organochlorine pesticides, pyrethroid insecticides, phthalates, bisphenol A, nicotine, and the primary metabolite of delta-9-tetrahydrocannabinol. Linear regression was used to estimate individual associations between chemicals and gestational age and birthweight z-scores (N ranging from 107 to 523). Mixture associations were estimated using quantile g-computation, principal component (PC) analyses, and hierarchical Bayesian kernel machine regression among complete cases (N = 86). RESULTS: Using quantile g-computation, increasing all chemical exposures by one quantile was modestly associated with a reduction in gestational age (mean change per quartile increase = -0.47, 95% CI = -1.56, 0.61) and birthweight z-scores (mean change per quartile increase = -0.49, 95% CI = -1.14, 0.15). All PCs were associated with a reduction in birthweight z-scores; associations were greatest in magnitude for the two PCs reflecting exposure to combined tobacco, insecticides, PBDEs, and phthalates. In single pollutant models, we observed inconsistent and largely non-significant associations. SIGNIFANCE: We conducted multiple targeted exposure assessment methods to quantify levels of environmental chemicals and leveraged mixture methods to quantify their joint effects on gestational age and birthweight z-scores. Our findings suggest that prenatal exposure to multiple classes of persistent and non-persistent chemicals is associated with reduced gestational age and birthweight z-scores in AAs. IMPACT: African Americans (AAs) experience higher rates of preterm birth and fetal growth restriction relative to other pregnant populations. Differential in utero exposure to environmental chemicals may partially explain these health disparities, as AAs are disproportionately exposed to environmental hazards. In the present study, we analyzed serum and urine samples for levels of 43 environmental chemicals. We used quantile g-computation, principal component analysis, and BKMR to assess associations between chemical exposure mixtures and adverse birth outcomes. Our findings suggest that prenatal exposure to multiple classes of chemicals is associated with reduced birthweight z-scores, a proxy for fetal growth, in AAs.

DNA methylation and general psychopathology in childhood: an epigenome-wide meta-analysis from the PACE consortium.

The general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N = 2178 and N = 2190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p = 8.58 × 10-8). We also identified a significant differentially methylated region (DMR) at school-age (p = 1.63 × 10-8), implicating the SHC Adaptor Protein 4 (SHC4) gene and the EP300-interacting inhibitor of differentiation 1 (EID1) gene that have been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder, schizophrenia, and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF.

Estimating the Relative Contribution of Environmental and Genetic Risk Factors to Different Aging Traits by Combining Correlated Variables into Weighted Risk Scores.

Genetic and exposomal factors contribute to the development of human aging. For example, genetic polymorphisms and exposure to environmental factors (air pollution, tobacco smoke, etc.) influence lung and skin aging traits. For prevention purposes it is highly desirable to know the extent to which each category of the exposome and genetic factors contribute to their development. Estimating such extents, however, is methodologically challenging, mainly because the predictors are often highly correlated. Tackling this challenge, this article proposes to use weighted risk scores to assess combined effects of categories of such predictors, and a measure of relative importance to quantify their relative contribution. The risk score weights are determined via regularized regression and the relative contributions are estimated by the proportion of explained variance in linear regression. This approach is applied to data from a cohort of elderly Caucasian women investigated in 2007-2010 by estimating the relative contribution of genetic and exposomal factors to skin and lung aging. Overall, the models explain 17% (95% CI: [9%, 28%]) of the outcome's variance for skin aging and 23% ([11%, 34%]) for lung function parameters. For both aging traits, genetic factors make up the largest contribution. The proposed approach enables us to quantify and rank contributions of categories of exposomal and genetic factors to human aging traits and facilitates risk assessment related to common human diseases in general. Obtained rankings can aid political decision making, for example, by prioritizing protective measures such as limit values for certain exposures.

DNA methylation as a potential mediator of the association between prenatal tobacco and alcohol exposure and child neurodevelopment in a South African birth cohort.

Prenatal tobacco exposure (PTE) and prenatal alcohol exposure (PAE) have been associated with an increased risk of delayed neurodevelopment in children as well as differential newborn DNA methylation (DNAm). However, the biological mechanisms connecting PTE and PAE, DNAm, and neurodevelopment are largely unknown. Here we aim to determine whether differential DNAm mediates the association between PTE and PAE and neurodevelopment at 6 (N = 112) and 24 months (N = 184) in children from the South African Drakenstein Child Health Study. PTE and PAE were assessed antenatally using urine cotinine measurements and the ASSIST questionnaire, respectively. Cord blood DNAm was measured using the EPIC and 450 K BeadChips. Neurodevelopment (cognitive, language, motor, adaptive behavior, socioemotional) was measured using the Bayley Scales of Infant and Toddler Development, Third Edition. We constructed methylation risk scores (MRS) for PTE and PAE and conducted causal mediation analysis (CMA) with these MRS as mediators. Next, we conducted a high-dimensional mediation analysis to identify individual CpG sites as potential mediators, followed by a CMA to estimate the average causal mediation effects (ACME) and total effect (TE). PTE and PAE were associated with neurodevelopment at 6 but not at 24 months. PTE MRS reached a prediction accuracy (R2) of 0.23 but did not significantly mediate the association between PTE and neurodevelopment. PAE MRS was not predictive of PAE (R2 = 0.006). For PTE, 31 CpG sites and eight CpG sites were identified as significant mediators (ACME and TE P < 0.05) for the cognitive and motor domains at 6 months, respectively. For PAE, 16 CpG sites and 1 CpG site were significant mediators for the motor and adaptive behavior domains at 6 months, respectively. Several of the associated genes, including MAD1L1, CAMTA1, and ALDH1A2 have been implicated in neurodevelopmental delay, suggesting that differential DNAm may partly explain the biological mechanisms underlying the relationship between PTE and PAE and child neurodevelopment.