Prenatal exposure to environmental phenols and phthalates and altered patterns of DNA methylation in childhood.

INTRODUCTION: Epigenetic marks are key biomarkers linking the prenatal environment to health and development. However, DNA methylation associations and persistence of marks for prenatal exposure to multiple Endocrine Disrupting Chemicals (EDCs) in human populations have not been examined in great detail. METHODS: We measured Bisphenol-A (BPA), triclosan, benzophenone-3 (BP3), methyl-paraben, propyl-paraben, and butyl-paraben, as well as 11 phthalate metabolites, in two pregnancy urine samples, at approximately 13 and 26 weeks of gestation in participants of the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study (N = 309). DNA methylation of cord blood at birth and child peripheral blood at ages 9 and 14 years was measured with 450K and EPIC arrays. Robust linear regression was used to identify differentially methylated probes (DMPs), and comb-p was used to identify differentially methylated regions (DMRs) in association with pregnancy-averaged EDC concentrations. Quantile g-computation was used to assess associations of the whole phenol/phthalate mixture with DMPs and DMRs. RESULTS: Prenatal BPA exposure was associated with 1 CpG among males and Parabens were associated with 10 CpGs among females at Bonferroni-level significance in cord blood. Other suggestive DMPs (unadjusted p-value < 1 × 10-6) and several DMRs associated with the individual phenols and whole mixture were also identified. A total of 10 CpG sites at least suggestively associated with BPA, Triclosan, BP3, Parabens, and the whole mixture in cord blood were found to persist into adolescence in peripheral blood. CONCLUSIONS: We found sex-specific associations between prenatal phenol exposure and DNA methylation, particularly with BPA in males and Parabens in females. Additionally, we found several DMPs that maintained significant associations with prenatal EDC exposures at age 9 and age 14 years.

Upper respiratory Streptococcus pneumoniae colonization among working-age adults with prevalent exposure to overcrowding.

Most pneumococcal disease occurs among infants and older adults and is thought to be driven by the transmission of Streptococcus pneumoniae from young children to these vulnerable age groups. However, pneumococcal disease outbreaks also affect non-elderly adults living or working in congregate, close-contact settings. Little is known about pneumococcal carriage in such populations. From July to November 2020, we collected saliva from low-income adult farmworkers in Monterey County, California, and tested for pneumococcal carriage following culture enrichment via quantitative PCR assays targeting the pneumococcal lytA and piaB genes. Participants were considered to carry pneumococci if lytA and piaB cycle threshold values were both below 40. Among 1,283 participants enrolled in our study, 117 (9.1%) carried pneumococci. Carriers tended more often than non-carriers to be exposed to children aged <5 years [odds ratio (OR) = 1.45 (0.95-2.20)] and overcrowding [OR = 1.48 (0.96-2.30) and 2.84 (1.20-6.73), respectively, for participants in households with >2-4 and >4 persons per bedroom vs ≤2 persons per bedroom]. Household overcrowding remained associated with increased risk of carriage among participants not exposed to children aged <5 years [OR = 2.05 (1.18-3.59) for participants living in households with >2 vs ≤2 persons per bedroom]. Exposure to children aged <5 years and overcrowding were each associated with increased pneumococcal density among carriers [piaB cT difference of 2.04 (0.36-3.73) and 2.44 (0.80-4.11), respectively]. While exposure to young children was a predictor of pneumococcal carriage, associations of overcrowding with increased prevalence and density of carriage in households without young children suggest that transmission also occurs among adults in close-contact settings.IMPORTANCEAlthough infants and older adults are the groups most commonly affected by pneumococcal disease, outbreaks are known to occur among healthy, working-age populations exposed to overcrowding, including miners, shipyard workers, military recruits, and prisoners. Carriage of Streptococcus pneumoniae is the precursor to pneumococcal disease, and its relation to overcrowding in adult populations is poorly understood. We used molecular methods to characterize pneumococcal carriage in culture-enriched saliva samples from low-income adult farmworkers in Monterey County, CA. While exposure to children in the household was an important risk factor for pneumococcal carriage, living in an overcrowded household without young children was an independent predictor of carriage as well. Moreover, participants exposed to children or overcrowding carried pneumococci at higher density than those without such exposures, suggesting recent transmission. Our findings suggest that, in addition to transmission from young children, pneumococcal transmission may occur independently among adults in overcrowded settings.

Childhood exposure to organophosphate pesticides: Functional connectivity and working memory in adolescents.

BACKGROUND: Early life exposure to organophosphate (OP) pesticides is linked with adverse neurodevelopment and brain function in children. However, we have limited knowledge of how these exposures affect functional connectivity, a measure of interaction between brain regions. To address this gap, we examined the association between early life OP pesticide exposure and functional connectivity in adolescents. METHODS: We administered functional near-infrared spectroscopy (fNIRS) to 291 young adults with measured prenatal or childhood dialkylphosphates (DAPs) in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a longitudinal study of women recruited during pregnancy and their offspring. We measured DAPs in urinary samples collected from mothers during pregnancy (13 and 26 weeks) and children in early life (ages 6 months, 1, 2, 3, and 5 years). Youth underwent fNIRS while they performed executive function and semantic language tasks during their 18-year-old visit. We used covariate-adjusted regression models to estimate the associations of prenatal and childhood DAPs with functional connectivity between the frontal, temporal, and parietal regions, and a mediation model to examine the role of functional connectivity in the relationship between DAPs and task performance. RESULTS: We observed null associations of prenatal and childhood DAP concentrations and functional connectivity for the entire sample. However, when we looked for sex differences, we observed an association between childhood DAPs and functional connectivity for the right interior frontal and premotor cortex after correcting for the false discovery rate, among males, but not females. In addition, functional connectivity appeared to mediate an inverse association between DAPs and working memory accuracy among males. CONCLUSION: In CHAMACOS, a secondary analysis showed that adolescent males with elevated childhood OP pesticide exposure may have altered brain regional connectivity. This altered neurofunctional pattern in males may partially mediate working memory impairment associated with childhood DAP exposure.

Residential proximity to agricultural pesticide use and cardiovascular disease risk factors among adult Latina women in California's Salinas Valley.

Cardiovascular disease is a leading cause of death worldwide. There is limited evidence that exposure to current-use pesticides may contribute to cardiovascular disease risk. We examined the association between residential proximity to the application of agricultural pesticides and cardiovascular risk factors among 484 adult women in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a cohort based in an agricultural region of California. Outcome assessment was completed between 2010 and 2013. Using participant residential addresses and California's Pesticide Use Reporting database, we estimated agricultural pesticide use within one km of residences during the 2-year period preceding outcome assessment. We used Bayesian Hierarchical Modeling to evaluate associations between exposure to 14 agricultural pesticides and continuous measures of waist circumference, body mass index, and blood pressure. Each 10-fold increase in paraquat application around homes was associated with increased diastolic blood pressure (ß=2.60 mm Hg, 95% Credible Interval (CrI): 0.27-4.89) and each 10-fold increase in glyphosate application was associated with increased pulse pressure (ß=2.26 mm Hg, 95% CrI: 0.09-4.41). No meaningful associations were observed for the other pesticides examined. Our results suggest that paraquat and glyphosate pesticides may affect cardiovascular disease development in women with chronic environmental exposure.

Organophosphate pesticide exposure and risk of SARS-CoV-2 infection.

Several studies have reported immune modulation by organophosphate (OP) pesticides, but the relationship between OP exposure and SARS-CoV-2 infection is yet to be studied. We used two different measures of OP pesticide exposure (urinary biomarkers (N = 154) and residential proximity to OP applications (N = 292)) to examine the association of early-childhood and lifetime exposure to OPs and risk of infection of SARS-CoV-2 using antibody data. Our study population consisted of young adults (ages 18-21 years) from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) Study, a longitudinal cohort of families from a California agricultural region. Urinary biomarkers reflected exposure from in utero to age 5 years. Residential proximity reflected exposures between in utero and age 16 years. SARS-CoV-2 antibodies in blood samples collected between June 2022 and January 2023 were detected via two enzyme linked immunosorbent assays, each designed to bind to different SARS-CoV-2 antigens. We performed logistic regression for each measure of pesticide exposure, adjusting for covariates from demographic data and self-reported questionnaire data. We found increased odds of SARS-CoV-2 infection among participants with higher urinary biomarkers of OPs in utero (OR = 1.94, 95% CI: 0.71, 5,58) and from age 0-5 (OR = 1.90, 95% CI: 0.54, 6.95).

Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10-8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

Pesticide exposure, birth size, and gestational age in the ISA birth cohort, Costa Rica.

Purpose: To examine associations of prenatal biomarkers of pesticide exposure with birth size measures and length of gestation among newborns from the Infants' Environmental Health (ISA) birth cohort, Costa Rica. Methods: We included 386 singleton liveborn newborns with data on birth size measures, length of gestation, and maternal urinary biomarkers of chlorpyrifos, synthetic pyrethroids, mancozeb, pyrimethanil, and 2, 4-D during pregnancy. We associated biomarkers of exposure with birth outcomes using multivariate linear regression and generalized additive models. Results: Concentrations were highest for ethylene thiourea (ETU, metabolite of mancozeb), median = 3.40; p10-90 = 1.90-6.79 µg/L, followed by 3,5,6-trichloro-2-pyridinol (TCP, metabolite of chlorpyrifos) p50 = 1.76 p10-90 = 0.97-4.36 µg/L, and lowest for 2,4-D (p50 = 0.33 p10-90 = 0.18-1.07 µg/L). Among term newborns (≥37 weeks), higher prenatal TCP was associated with lower birth weight and smaller head circumference (e.g., ß per 10-fold-increase) during the second half of pregnancy = -129.6 (95% confidence interval [CI] = -255.8, -3.5) grams, and -0.61 (95% CI = -1.05, -0.17) centimeters, respectively. Also, among term newborns, prenatal 2,4-D was associated with lower birth weight (ß per 10-fold-increase = -125.1; 95% CI = -228.8, -21.5), smaller head circumference (ß = -0.41; 95% CI = -0.78, -0.03), and, during the second half of pregnancy, with shorter body length (ß = -0.58; 95% CI = -1.09, -0.07). Furthermore, ETU was nonlinearly associated with head circumference during the second half of pregnancy. Biomarkers of pyrethroids and pyrimethanil were not associated with birth size, and none of the biomarkers explained the length of gestation. Conclusions: Prenatal exposure to chlorpyrifos and 2,4-D, and, possibly, mancozeb/ETU, may impair fetal growth.

Prenatal exposure to polybrominated diphenyl ether (PBDE) and child neurodevelopment: The role of breastfeeding duration.

BACKGROUND: Prenatal and early-life exposure to polybrominated diphenyl ethers (PBDEs) is associated with detrimental and irreversible neurodevelopmental health outcomes during childhood. Breastfeeding may be a child's largest sustained exposure to PBDE- potentially exacerbating their risk for adverse neurodevelopment outcomes. However, breastfeeding has also been associated with positive neurodevelopment. Our study investigates if breastfeeding mitigates or exacerbates the known adverse effects of prenatal exposure to PBDEs and child neurodevelopment. METHODS: Participants included 321 mother-infant dyads from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a longitudinal birth cohort in California. PBDE concentrations were measured in maternal serum blood samples collected during pregnancy or at delivery. Using generalized estimated equations (GEE), we estimated associations of PBDE concentrations with children's attention, executive function, and cognitive scores assessed longitudinally between 7 and 12 years of age, stratified by duration of exclusive and complementary breastfeeding. RESULTS: We observed that higher maternal prenatal PBDE concentrations were associated with poorer executive function among children who were complementary breastfed for a shorter duration compared to children breastfed for a longer duration; preservative errors (ß for 10-fold increase in complementary breastfeeding <7 months = -6.6; 95 % Confidence Interval (CI): -11.4, -1.8; ß ≥ 7 months = -5.1; 95 % CI: -10.2, 0.1) and global executive composition (ß for 10-fold increase <7 months = 4.3; 95 % CI: 0.4, 8.2; ß for 10-fold increase ≥7 months = 0.6; 95 % CI: -2.8, 3.9). CONCLUSIONS: Prolonged breastfeeding does not exacerbate but may mitigate some previously observed negative associations of prenatal PBDE exposure and child neurodevelopment.

Association between prenatal exposure to indoor residual spraying insecticides and infection rates among South African children participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE).

In 2021, 53 countries conducted indoor residual spraying (IRS), the application of insecticides such as dichlorodiphenyl trichloroethane (DDT) or pyrethroids to the walls of homes to control malaria. Animal studies show that these insecticides can increase susceptibility to infections but only one human study was conducted in a population from an area where IRS is applied. The aim of the present study was thus to investigate whether maternal exposure to DDT, its breakdown product dichlorodiphenyl dichloroethylene (DDE) or pyrethroid insecticides is associated with symptoms of infection among children living in a region of South Africa were IRS is conducted annually. As part of the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) we measured maternal serum concentrations of DDT and DDE, and urinary concentrations of four pyrethroid metabolites in peripartum samples. Poisson regression models with robust variance estimates were used to investigate associations with the rates of infection symptoms between ages 3.5-5 years among 629 children as assessed based on caregiver interviews. Multiple pyrethroid metabolites were associated with infection symptoms. For instance, cis-DBCA was associated with increased rates of ear infection (Incidence Rate Ratio for a 10-fold increase (IRR10) = 1.4; 95 % Confidence Interval (CI) = 1.0, 2.1) and persistent diarrhea (IRR10 = 2.1; 95 % CI = 1.2, 3.9), trans-DCCA was associated with increased rates of colds in children (IRR10 = 1.3; 95 % CI = 1.0, 1.6) and persistent fever (IRS10 = 1.4; 95 % CI = 1.0, 2.0), and 3-PBA was associated with increased rates of persistent fever (IRR10 = 1.8; 95 % CI = 1.0, 3.0). We found limited evidence of association between maternal DDE and DDT serum concentrations and infection symptoms. Results suggest that prenatal exposure to pyrethroid insecticides may be associated with infections among children from an area where IRS is conducted.

Association of pesticide exposure with neurobehavioral outcomes among avocado farmworkers in Mexico.

BACKGROUND AND AIM: To date, few studies have focused on the health effects of pesticide exposure among avocado farmworkers. We examined the association of exposure to insecticides, fungicides, and herbicides with cognitive and mental health outcomes among these avocado workers from Michoacan, Mexico. MATERIALS AND METHODS: We conducted a cross-sectional study of 105 avocado farmworkers between May and August 2021. We collected data on self-reported pesticide use during the 12 months prior to the baseline survey and estimated annual exposure-intensity scores (EIS) using a semi-quantitative exposure algorithm. We calculated specific gravity adjusted average concentrations of 12 insecticide, fungicide, or herbicide metabolites measured in urine samples collected during two study visits (8-10 weeks apart). We assessed participants' cognitive function and psychological distress using the NIH Toolbox Cognition Battery and the Brief Symptom Inventory 18 (BSI-18), respectively. We examined individual associations of EIS and urinary pesticide metabolites with neurobehavioral outcomes using generalized linear regression models. We also implemented Bayesian Weighted Quantile Sum (BWQS) regression to evaluate the association between a pesticide metabolite mixture and neurobehavioral outcomes. RESULTS: In individual models, after adjusting for multiple comparisons, higher concentrations of hydroxy-tebuconazole (OH-TEB, metabolite of fungicide tebuconazole) were associated with higher anxiety (IRR per two-fold increase in concentrations = 1.26, 95% CI:1.08, 1.48) and Global Severity Index (GSI) (IRR = 1.89, 95% CI:1.36, 2.75) scores, whereas higher concentrations of 3,5,6-trichloro-2-pyridinol (TCPy, metabolite of chlorpyrifos) were associated with lower GSI scores (IRR = 0.69, 95% CI: 0.56, 0.85). In BWQS analyses, we found evidence of a mixture association of urinary pesticide metabolites with higher anxiety (IRR = 1.72, 95% CrI: 1.12, 2.55), depression (IRR = 4.60, 95% CrI: 2.19, 9.43), and GSI (IRR = 1.99, 95% CrI: 1.39, 2.79) scores. OH-TEB and hydroxy-thiabendazole (metabolite of fungicide thiabendazole) combined contributed 54%, 40%, and 54% to the mixture effect in the anxiety symptoms, depression symptoms, and overall psychological distress models, respectively. CONCLUSIONS: We found that exposure to tebuconazole and thiabendazole, fungicides whose effects have been rarely studied in humans, may be associated with increased psychological distress among avocado farmworkers. We also observed that exposure to chlorpyrifos may be associated with decreased psychological distress.

Prenatal current-use pesticide exposure and children's neurodevelopment at one year of age in the Infants' Environmental Health (ISA) birth cohort, Costa Rica.

BACKGROUND: Pesticide exposure may affect young children's neurodevelopment, but only few cohort studies have addressed possible effects of non-organophosphate pesticides. OBJECTIVE: We evaluated associations between prenatal current-use pesticide exposure and neurodevelopmental outcomes among 1-year-old children from the Infants' Environmental Health (ISA) birth cohort. METHODS: To determine prenatal pesticide exposure, we measured biomarkers of pyrimethanil, chlorpyrifos, synthetic pyrethroids, and 2,4-D in urine samples among 355 women, 1-3 times during pregnancy. One-year post-partum, we evaluated children's neurodevelopment with the Bayley Scales of Infant and Toddler Development 3rd edition (BSID-III). We assessed associations between exposures and neurodevelopmental outcomes (composite and z-scores) using single-chemical linear regression models adjusted for possible confounders (maternal education, parity, sex, gestational age at birth, child age, HOME-score, location of assessment, biomarkers of mancozeb), and studied effect-modification by sex. We evaluated non-linear associations of multiple pesticide exposures with Bayesian kernel machine regression (BKMR). RESULTS: We found higher prenatal urinary 2,4-D concentrations were associated with lower language (ßper ten-fold increase = -2.0, 95 % confidence interval (CI) = -3.5, -0.5) and motor (ßper ten-fold increase = -2.2, 95 %CI = -4.2, -0.1) composite scores among all children. Also, higher chlorpyrifos exposure [measured as urinary 3,5,6-trichloro-2-pyridinol (TCPy)] was associated with lower cognitive composite scores (ßper ten-fold increase = -1.9, 95 %CI = -4.7, 0.8), and lower motor composite scores among boys (ßper ten-fold increase = -3.8, 95 % CI = -7.7, 0.1) but not girls (ßper ten-fold increase = 2.3, 95 %CI = -1.6, 6.3, pINT = 0.11). Finally, higher pyrimethanil was associated with lower language abilities among girls, but not boys. Pyrethroid metabolite concentrations did not explain variability in BSID-III composite scores. Associations were similar for BSID-III z-scores, and we found no evidence for non-linear associations or mixture effects. DISCUSSION: Prenatal exposure to common-use pesticides may affect children's neurodevelopment at 1-year of age, some effects may be sex-specific.

SARS-CoV-2 infection and long COVID among California farmworkers.

PURPOSE: The purpose of this cross-sectional study was to determine the prevalence of long COVID and identify its clinical manifestations among farmworkers in California. METHODS: We collected data on sociodemographic characteristics, anthropometrics, clinical chemistries and anti-SARS-CoV-2 immunoglobulin G antibodies, self-reported SARS-CoV-2 infection history, and standardized health tests and scales from 297 farmworkers in California between February and July 2022. RESULTS: Most participants were born in Mexico or Central America, had less than a high school diploma, and were overweight or obese. The prevalence of long COVID (defined as self-reported SARS-CoV-2 infection with symptoms >28 days) among farmworkers with a suspected or test-confirmed infection was 61.8%. Participants with long COVID had higher mean [95% CI] body mass index (32.9 [31.6-34.1]) and high-sensitivity C-reactive protein levels (4.8 [3.7, 6.0]) than those with no COVID-19 history (30.5 [29.3-31.7], and 3.3 [2.2, 4.3], respectively). Farmworkers with long COVID also reported greater fatigue, dyspnea, taste and smell problems, and overall poorer mental and physical health, than those with no COVID-19 history. Farmworkers with long COVID had increased odds of functional limitations compared to those with a self-reported SARS-CoV-2 infection with symptoms ≤28 days (OR [95% CI]: 7.46 [3.26, 17.09]). CONCLUSIONS: A significant proportion of farmworkers experience long COVID with persistent symptoms that limit their ability to perform their work. A comprehensive approach that addresses the unique needs and challenges of farmworkers is warranted given this population's high prevalence of long COVID and the essential nature of their work.

Maternal Adverse Childhood Experiences and Young Adult Latino Children's Mental Health.

INTRODUCTION: Maternal adverse childhood experiences have been linked to a variety of negative health outcomes in young children; however, young adults and, specifically, young adult Latinos have been vastly understudied. This study investigates the intergenerational pathway between maternal adverse childhood experiences and behavioral health outcomes of their young adult children, as mediated through young adults' own adverse childhood experiences and maternal depression. METHODS: Structural equation modeling was used to analyze data (in 2023) from mothers and their young adult children (n=398 dyads) enrolled in the Center for the Health Assessment of Mothers and Children of Salinas cohort, a primarily Latino agricultural sample. Maternal and young adult adverse childhood experiences were self-reported retrospectively during a visit at the age of 18 years (2018-2020). Young adult- and maternal-reported internalizing and maternal-reported externalizing behaviors were assessed at the age of 18 years with the Behavior Assessment for Children, second edition. Maternal depression was assessed during a visit at the age of 9 years (2010-2012) using the Center for Epidemiologic Studies Depression Scale. RESULTS: Maternal and young adult adverse childhood experiences were weakly but statistically significantly correlated (r=0.22). Maternal adverse childhood experiences were statistically significantly associated with maternal-reported youth internalizing symptoms (ß=0.29; 95% CI=0.19, 0.38; p<0.001) and externalizing symptoms (ß=0.24; 95% CI=0.14, 0.33; p<0.001) and marginally associated with youth-reported internalizing symptoms (ß=0.08; 95% CI= -0.02, 0.18; p=0.13). Youth adverse childhood experiences and maternal depressive symptomatology mediated the associations between maternal adverse childhood experiences and young adult outcomes. CONCLUSIONS: Findings demonstrate the potential impacts of adversity across generations in Latino immigrant families, an understudied population. Understanding the mechanisms and factors associated with these pathways may lead to strategies that prevent poor mental health outcomes in young adults.

Maternal exposure to pyrethroid insecticides during pregnancy and respiratory allergy symptoms among children participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE).

BACKGROUND: Pyrethroid insecticides use for indoor residual spraying (IRS) in malaria-endemic areas results in high levels of exposure to local populations. Pyrethroids may cause asthma and respiratory allergies but no prior study has investigated this question in an IRS area. METHODS: We measured maternal urinary concentrations of pyrethroid metabolites (cis-DBCA, cis-DCCA, trans-DCCA, 3-PBA) in samples collected at delivery from 751 mothers participating in the Venda Health Examination of Mothers, Babies, and their Environment (VHEMBE), a birth cohort study based in Limpopo, South Africa. At 3.5-year and 5-year follow-up visits, caregivers of 647 and 620 children, respectively, were queried about children's respiratory allergy symptoms based on validated instruments. We applied marginal structural models for repeated outcomes to estimate associations between biomarker concentrations and asthma diagnosis as well as respiratory allergy symptoms at ages 3.5 and 5 years. RESULTS: We found that a10-fold increase in maternal urinary cis-DCCA, trans-DCCA and 3-PBA concentrations were associated with more than a doubling in the risk of doctor-diagnosed asthma (cis-DCCA: RR = 2.1, 95% CI = 1.3, 3.3; trans-DCCA: RR = 2.1, 95% CI = 1.1, 3.9; 3-PBA: RR = 2.4, 95% CI = 1.0, 5.8) and an about 80% increase in the risk of wheezing or whistling in the chest (cis-DCCA: RR = 1.8, 95% CI = 1.1, 3.0; trans-DCCA: RR = 1.7, 95% CI = 1.1, 2.6; 3-PBA: RR = 1.8, 95% CI = 1.0, 3.3) and suspected asthma (cis-DCCA: RR = 1.8, 95% CI = 1.1, 3.1; trans-DCCA: RR = 1.8, 95% CI = 1.1, 2.8). We also observed that higher concentrations of cis-DBCA and 3-PBA were related to increases in the risks of dry cough at night (RR = 3.5, 95% CI = 1.3, 9.5) and seasonal rhinoconjunctivitis (RR = 2.0, 95% CI = 1.1, 3.9), respectively. CONCLUSION: Maternal exposure to pyrethroids may increase the risk of asthma and other respiratory allergy symptoms among preschool children from an IRS area.

Prenatal and childhood exposure to organophosphate pesticides and functional brain imaging in young adults.

BACKGROUND: Early life exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment from infancy to adolescence. In our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort, we previously reported that residential proximity to OP use during pregnancy was associated with altered cortical activation using functional near infrared spectroscopy (fNIRS) in a small subset (n = 95) of participants at age 16 years. METHODS: We administered fNIRS to 291 CHAMACOS young adults at the 18-year visit. Using covariate-adjusted regression models, we estimated associations of prenatal and childhood urinary dialkylphosphates (DAPs), non-specific OP metabolites, with cortical activation in the frontal, temporal, and parietal regions of the brain during tasks of executive function and semantic language. RESULTS: There were some suggestive associations for prenatal DAPs with altered activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during a task of cognitive flexibility (ß per ten-fold increase in DAPs = 3.37; 95% CI: -0.02, 6.77 and ß = 3.43; 95% CI: 0.64, 6.22, respectively) and the inferior and superior frontal pole/dorsolateral prefrontal cortex of the right hemisphere during the letter retrieval working memory task (ß = -3.10; 95% CI: -6.43, 0.22 and ß = -3.67; 95% CI: -7.94, 0.59, respectively). We did not observe alterations in cortical activation with prenatal DAPs during a semantic language task or with childhood DAPs during any task. DISCUSSION: We observed associations of prenatal OP concentrations with mild alterations in cortical activation during tasks of executive function. Associations with childhood exposure were null. This is reasonably consistent with studies of prenatal OPs and neuropsychological measures of attention and executive function found in CHAMACOS and other birth cohorts.

Racial and Ethnic Disparities in Phthalate Exposure and Preterm Birth: A Pooled Study of Sixteen U.S. Cohorts.

BACKGROUND: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. OBJECTIVES: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity. METHODS: We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth. RESULTS: In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants. CONCLUSIONS: Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Maternal adverse childhood experiences (ACEs) and DNA methylation of newborns in cord blood.

BACKGROUND: Adverse childhood experiences (ACEs) increase the risk of poor health outcomes later in life. Psychosocial stressors may also have intergenerational health effects by which parental ACEs are associated with mental and physical health of children. Epigenetic programming may be one mechanism linking parental ACEs to child health. This study aimed to investigate epigenome-wide associations of maternal preconception ACEs with DNA methylation patterns of children. In the Center for the Health Assessment of Mothers and Children of Salinas study, cord blood DNA methylation was measured using the Illumina HumanMethylation450 BeadChip. Preconception ACEs, which occurred during the mothers' childhoods, were collected using a standard ACE questionnaire including 10 ACE indicators. Maternal ACE exposures were defined in this study as (1) the total number of ACEs; (2) the total number of ACEs categorized as 0, 1-3, and > 4; and (3) individual ACEs. Associations of ACE exposures with differential methylated positions, regions, and CpG modules determined using weighted gene co-expression network analysis were evaluated adjusting for covariates. RESULTS: Data on maternal ACEs and cord blood DNA methylation were available for 196 mother/newborn pairs. One differential methylated position was associated with maternal experience of emotional abuse (cg05486260/FAM135B gene; q value < 0.05). Five differential methylated regions were significantly associated with the total number of ACEs, and 36 unique differential methylated regions were associated with individual ACEs (Sidák p value < 0.05). Fifteen CpG modules were significantly correlated with the total number of ACEs or individual ACEs, of which 8 remained significant in fully adjusted models (p value < 0.05). Significant modules were enriched for pathways related to neurological and immune development and function. CONCLUSIONS: Maternal ACEs prior to conception were associated with cord blood DNA methylation of offspring at birth. Although there was limited overlap between differential methylated regions and CpGs in modules associated with ACE exposures, statistically significant regions and networks were related to genes involved in neurological and immune function. Findings may provide insights to pathways linking psychosocial stressors to health. Further research is needed to understand the relationship between changes in DNA methylation and child health.

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

Prenatal and Childhood Exposure to Organophosphate Pesticides and Behavior Problems in Adolescents and Young Adults in the CHAMACOS Study.

BACKGROUND: We previously reported associations of prenatal exposure to organophosphate (OP) pesticides with poorer neurodevelopment in early childhood and at school age, including poorer cognitive function and more behavioral problems, in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a birth cohort study in an agriculture community. OBJECTIVE: We investigated the extent to which early-life exposure to OP pesticides is associated with behavioral problems, including mental health, in youth during adolescence and early adulthood. METHODS: We measured urinary dialkylphosphates (DAPs), nonspecific OP metabolites, in urine samples collected from mothers twice during pregnancy (13 and 26 wk) and at five different times in their children (ages 6 months to 5 y). We assessed maternal report and youth report of externalizing and internalizing behavior problems using the Behavior Assessment System for Children, 2nd edition (BASC-2), when the youth were ages 14, 16, and 18 y. Because there was evidence of nonlinearity, we estimated associations across quartiles of DAPs and modeled repeated outcome measures using generalized estimating equations. RESULTS: There were 335 youths with prenatal maternal DAP measures and 14-. 16-, or 18-y BASC-2 scores. Prenatal maternal DAP concentrations (specific gravity-adjusted median, Q1-Q3=159.4, 78.7-350.4 nmol/L) were associated with higher T-scores (more behavior problems) from maternal report, including more hyperactivity [fourth vs. first quartile of exposure ß=2.32; 95% confidence interval (CI): 0.18, 4.45], aggression (ß=1.90; 95% CI: 0.15, 3.66), attention problems (ß=2.78; 95% CI: 0.26, 5.30), and depression (ß=2.66; 95% CI: 0.08, 5.24). Associations with youth report of externalizing problems were null, and associations with depression were suggestive (fourth vs. first quartile of exposure ß=2.15; 95% CI: -0.36, 4.67). Childhood DAP metabolites were not associated with behavioral problems. DISCUSSION: We found associations of prenatal, but not childhood, urinary DAP concentrations with adolescent/young adult externalizing and internalizing behavior problems. These findings are consistent with prior associations we have reported with neurodevelopmental outcomes measured earlier in childhood in CHAMACOS participants and suggests that prenatal exposure to OP pesticides may have lasting effects on the behavioral health of youth as they mature into adulthood, including their mental health. https://doi.org/10.1289/EHP11380.

Associations between prenatal phthalate exposure and childhood epigenetic age acceleration.

BACKGROUND: Phthalates, a group of pervasive endocrine-disrupting chemicals found in plastics and personal care products, have been associated with a wide range of developmental and health outcomes. However, their impact on biomarkers of aging has not been characterized. We tested associations between prenatal exposure to 11 phthalate metabolites on epigenetic aging in children at birth, 7, 9, and 14 years of age. We hypothesized that prenatal phthalate exposure will be associated with epigenetic age acceleration measures at birth and in early childhood, with patterns dependent on sex and timing of DNAm measurement. METHODS: Among 385 mother-child pairs from the CHAMACOS cohort, we measured DNAm at birth, 7, 9, and 14 years of age, and utilized adjusted linear regression to assess the association between prenatal phthalate exposure and Bohlin's Gestational Age Acceleration (GAA) at birth and Intrinsic Epigenetic Age Acceleration (IEAA) throughout childhood. Additionally, quantile g-computation was utilized to assess the effect of the phthalate mixture on GAA at birth and IEAA throughout childhood. RESULTS: We found a negative association between prenatal di (2-ethylhexyl) phthalate (DEHP) exposure and IEAA among males at age 7 (-0.62 years; 95% CI:-1.06 to -0.18), and a marginal negative association between the whole phthalate mixture and GAA among males at birth (-1.54 days, 95% CI: -2.79 to -0.28), while most other associations were nonsignificant. CONCLUSIONS: Our results suggest that prenatal exposure to certain phthalates is associated with epigenetic aging in children. Additionally, our findings suggest that the influence of prenatal exposures on epigenetic age may only manifest during specific periods of child development, and studies relying on DNAm measurements solely from cord blood or single time points may overlook potential relationships.