Programming Research In Obesity, Growth, Environment And Social Stressors Research Articles

Associations between prenatal metal and metalloid mixtures in teeth and reductions in childhood lung function

BackgroundMetal(oid)s have been cross-sectionally associated with lung function outcomes in childhood but there is limited data on their combined effects starting in utero. Child sex may further modify these effects. ObjectiveExamine associations between in utero and early life exposure to metals assessed via novel dentine biomarkers and childhood lung function and explore effect modification by child sex. MethodsAnalyses included 291 children enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a longitudinal birth cohort study in Mexico City. Weekly dentine levels of arsenic (As), cadmium (Cd), cobalt (Co), copper (Cu), manganese (Mn), nickel (Ni), and lead (Pb) were measured from 15 weeks pre-birth to 15 weeks post birth in deciduous children's teeth. Lung function was tested at ages 8–14 years and then modeled as age, height and sex adjusted z-scores. Associations were modeled using lagged weighted quantile sum (LWQS) regression to evaluate the potential for a time-varying mixture effect adjusting for maternal age and education at enrollment and exposure to environmental tobacco smoke in pregnancy. Models were also stratified by sex. ResultsWe identified a window of susceptibility at 12–15 weeks pre-birth in which the metal mixture was associated with lower FVC z-scores in children aged 8–14 years. Cd and Mn were the largest contributors to the mixture effect (70 %). There was also some evidence of effect modification by sex, in which the mean weights and weighted correlations over the identified window was more evident in males when compared to females. In the male stratum, Cd, Mn and additionally Pb also dominated the mixture association. ConclusionsPrenatal metal(oid) exposure was associated with lower lung function in childhood. These findings underscore the need to consider both mixtures and windows of susceptibility to fully elucidate effects of prenatal metal(oid) exposure on childhood lung function.

Longitudinal associations between early-life fluoride exposures and cardiometabolic outcomes in school-aged children

Background/AimFluoride is a natural mineral present in food, water, and dental products, constituting ubiquitous long-term exposure in early childhood and across the lifespan. Experimental evidence shows fluoride-induced lipid disturbances with potential implications for cardiometabolic health. However, epidemiological studies are scarce. For the first time, we evaluated associations between repeated fluoride measures and cardiometabolic outcomes in children. MethodsWe studied ∼ 500 Mexican children from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort with measurements on urinary fluoride at age 4, and dietary fluoride at ages 4, 6, and 8 years approximately. We used covariate-adjusted linear mixed-effects and linear regression models to assess fluoride associations with multiple cardiometabolic outcomes (ages 4–8): lipids (total cholesterol, HDL, LDL, and triglycerides), glucose, HbA1c, adipokines (leptin and adiponectin), body fat, and age- and sex-specific z-scores of body mass index (zBMI), waist circumference, and blood pressure. ResultsDietary fluoride intake at age 4 was associated with annual increases in triglycerides [β per-fluoride-doubling = 2.02 (95 % CI: 0.37, 3.69)], cholesterol [β = 1.46 (95 % CI: 0.52, 2.39)], HDL [β = 0.39 (95 % CI: 0.02, 0.76)], LDL [β = 0.87 (95 % CI: 0.02, 1.71)], and HbA1c [β = 0.76 (95 % CI: 0.28, 1.24)], and decreased leptin [β = -3.58 (95 % CI: −6.34, −0.75)] between the ages 4 and 8. In cross-sectional analyses at age 8, higher tertiles of fluoride exposure were associated with increases in zBMI, triglycerides, glucose, and leptin (p-tertile trend < 0.05). Stronger associations were observed in boys at year 8 and in girls prior to year 8 (p-sex interaction < 0.05). Fewer but consistent associations were observed for urinary fluoride at age 4, indicating increased annual changes in HDL and HbA1c with higher fluoride levels. ConclusionDietary fluoride exposures in early- and mid-childhood were associated with adverse cardiometabolic outcomes in school-aged children. Further research is needed to elucidate whether these associations persist at later ages.

Prenatal lead exposure is negatively associated with the gut microbiome in childhood.

Metal exposures are associated with gut microbiome (GM) composition and function, and exposures early in development may be particularly important. Considering the role of the GM in association with many adverse health outcomes, understanding the relationship between prenatal metal exposures and the GM is critically important. However, there is sparse knowledge of the association between prenatal metal exposure and GM later in childhood. This analysis aims to identify associations between prenatal lead (Pb) exposure and GM composition and function in children 9-11 years old. Data come from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort based in Mexico City, Mexico. Prenatal metal concentrations were measured in maternal whole blood drawn during the second and third trimesters of pregnancy. Stool samples collected at 9-11 years old underwent metagenomic sequencing to assess the GM. This analysis uses multiple statistical modeling approaches, including linear regression, permutational analysis of variance, weighted quantile sum regression (WQS), and individual taxa regressions, to estimate the association between maternal blood Pb during pregnancy and multiple aspects of the child GM at 9-11 years old, adjusting for relevant confounders. Of the 123 child participants in this pilot data analysis, 74 were male and 49 were female. Mean prenatal maternal blood Pb was 33.6 (SE = 2.1) ug/L and 34.9 (SE = 2.1) ug/L at second and third trimesters, respectively. Analysis suggests a consistent negative relationship between prenatal maternal blood Pb and the GM at age 9-11, including measures of alpha and beta diversity, microbiome mixture analysis, and individual taxa. The WQS analysis showed a negative association between prenatal Pb exposure and the gut microbiome, for both second and third trimester exposures (2Tβ = -0.17, 95%CI = [-0.46,0.11]; 3Tβ = -0.17, 95%CI = [-0.44,0.10]). Ruminococcus gnavus, Bifidobacterium longum, Alistipes indistinctus, Bacteroides caccae, and Bifidobacterium bifidum all had weights above the importance threshold from 80% or more of the WQS repeated holdouts in association with both second and third trimester Pb exposure. Pilot data analysis suggests a negative association between prenatal Pb exposure and the gut microbiome later in childhood; however, additional investigation is needed.

1097-P: Association between Adipokines and Glycemia in Children under Age 8—The PROGRESS Cohort of Mexico

Background: The increased incidence of type 2 diabetes is closely linked to obesity, in which an accumulation of adipocytes leads to the dysregulated production of adipokines. In adults, several adipokines contribute to the development of glycemic dysregulation, however, the role of adipokines on childhood glycemia is poorly understood. We examine the longitudinal association between adipokines and glycemia using multiple timepoint data from children in Mexico City. Methods: Children from the Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) cohort (948 children, 52% male) were followed longitudinally after birth. Leptin, adiponectin, glucose, and HbA1c were measured at 4, 6, and 8 years, and fasting insulin at 8 years. Adiponectin to leptin ratio (ALR) and HOMA2 (B/IR/S) indices were computed. Longitudinal association between adipokines and each of glucose and HbA1c was examined by linear mixed models. Association between adipokines and insulin and the HOMAs at age 8 was examined by multivariable linear regression. All models were adjusted for maternal and child covariates. Results: Between ages 4 and 8 years, average levels of leptin dropped from 15.7 to 13.7 ug/mL; adiponectin increased from 3.1 to 10.8 ng/mL; and ALR dropped from 9.1 to 3.1 ug/ng. Longitudinally, across timepoints 4, 6, and 8 years after birth, there was no association between adipokines and glycemia. However, the cross-sectional analysis at age 8 years found an association between leptin and insulin (1.03, 95% CI: 1.00, 1.07), HOMA2-B (1.02, 95% CI: 1.00, 1.04), HOMA2-IR (1.03, 95% CI: 1.00, 1.07), and HOMA2-S (0.97, 95% CI: 0.94, 0.99). Similar associations were observed in males and females. Conclusion: In this prepubertal cohort, leptin was associated with insulin and with HOMA indices at age 8. Further investigation is needed to understand the role of adipokines in the development of T2DM in children and the risk factors that may alter adipokine metabolism. Disclosure Y.S.Beyh: None. R.O.Wright: None. M.M.Tellez-rojo: None. A.Baccarelli: None. H.Wu: None. K.Narayan: None. L.R.Staimez: None. U.Ramakrishnan: None. M.K.Bhasin: None. M.Tolentino dolores: None. G.Estrada-gutierrez: None. M.Yitshak sade: None. Funding National Institute of Environmental Health Sciences (R01ES032242, R01ES021357, R01ES013744, P30ES009089)

Resting-state functional connectivity patterns are associated with metal mixture exposure in young adolescents

Background and Aim. Early-life metal mixture exposure may increase the risk for anxiety and depression in adolescence. The neural circuitry subserving internalizing phenotypes begins developing in utero and is vulnerable to early-life exposures. Resting state functional magnetic resonance imaging (rs-fMRI) provides a novel tool to examine underlying mechanisms of metal-associated neurodevelopmental outcomes. We investigate relationships between early-life metal exposure and functional connectivity in pre-adolescents. Methods. In preliminary analysis of 67 children (8-14years; 34 females) enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, we estimated weekly exposure (14th week gestation through one year of age) to 15 metals (Ba, Bi, Cd, Co, Cr, Cu, Li, Mg, Mn, Mo, Ni, Pb, Sn, Sr, Zn) in deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. Using graph theory analysis of rs-fMRI data, we computed global and local efficiency (GE, LE) and eigenvector centrality (EC) in 111 brain areas (Harvard Oxford Atlas). We used lagged weighted quantile sum (lWQS) regression to examine time-varying associations between metal mixtures and GE, LE or EC in the whole brain and anterior cingulate cortex (ACC), globus pallidus (GP), and insula, adjusting for sex and age. Results. We observed prenatal and postnatal windows between the metal mixture and LE; -13 to 4 weeks, peak βLE (week -2) = -0.23, 95%CI -0.02, -0.45 and 16 to 43 weeks; peak βLE (week 42) = -0.42, 95%CI -0.13, -0.70 and one prenatal window for GE at -18 to -11 weeks, peak βGE (week -18) = -0.35, 95%CI -0.07, -0.64. The metal mixture was significantly associated with decreased EC in the ACC, GP and insula at different critical windows spanning gestation and infancy. Conclusions. Our results combining lWQS modeling with graph theory analysis of rs-fMRI may inform mechanistic understanding of environmentally-associated neurodevelopmental outcomes.

Early-life critical windows of metal exposure associated with internalizing symptoms in young adolescents

Introduction and Aim: Internalizing disorders, such as anxiety and depression, affect 10 – 20% of children and increase the risk for later-life psychopathology. The neural circuitry subserving internalizing phenotypes begins developing in utero and is vulnerable to early-life environmental exposures. Although early-life exposure to metals can adversely impact children’s neurodevelopment and have lifelong impacts on mental health, little is known about critical windows to metal exposures and adolescent internalizing disorders. In this study, we hypothesized that early-life exposure to a mixture of metals is associated with increased internalizing problems in early adolescence. Methods: Among 431 (8-12 years; 216 females) pre-adolescents enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) longitudinal birth cohort study in Mexico City, we estimated weekly concentrations of 15 metals in naturally shed deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry (i.e., Ba, Bi, Cd, Co, Cr, Cu, Li, Mg, Mn, Mo, Ni, Pb, Sn, Sr, and Zn) from the 14th gestation week through one year of age). Internalizing problems were assessed using the Behavior Assessment System for Children, 2nd edition (BASC-2). We used lagged weighted quantile sum (lWQS) regression to estimate a time-varying mixture effect of multiple metals on internalizing problems. Models were adjusted for age and sex. Results: A higher metal mixture index in the 22nd-43rd postnatal weeks was associated with increased internalizing problems (maximum β = 0.37 [95% CI 0.06, 0.69]), driven mainly by Mg, As, Sn, and Bi. Conclusions: This study supports the hypothesis that mixed metal exposure during specific critical windows in early life may associate with mental health disorders in childhood and adolescence. Our lWQS modeling approach and results may inform the role of exposure timing in driving neurodevelopmental outcomes, thereby pointing to future optimal, efficient, and properly timed public health interventions.

Early life metal exposure is associated with reduced fractional anisotropy in the corpus callosum in children

Background: The corpus callosum (CC) is the largest white matter structure in the brain, connecting the left and right hemispheres into functional networks subserving cognition and behavior. Neuroimaging studies demonstrate rapid CC development during the first years of life. During these early-life critical windows, the CC is vulnerable to perturbation by neurotoxicants including heavy metals. Most environmental studies consider single neurotoxicant exposures at a single time point, potentially missing the effects of joint exposure across a developmental stage. Here, we investigated associations between early life metal mixture exposure and CC white matter microstructure integrity in children. Methods: In a preliminary analysis of 47 children (8-13 years; 22 females) enrolled in a neuroimaging substudy within the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, we estimated weekly exposure (22nd-week gestation through 43rd week postnatal) to manganese (Mn), zinc (Zn), and lead (Pb) using laser ablation-inductively coupled plasma-mass spectrometry of teeth. We estimated CC white matter microstructure integrity using fractional anisotropy (FA) from diffusion tensor imaging (DTI) acquired in a 3T Siemens scanner. We used lagged weighted quantile sum (lWQS) regression to estimate the time-varying mixture effect on FA in the CC. Results: A higher metal mixture index in the 24th-43rd postnatal weeks was associated with decreased FA in the CC genu, body, and splenium (maximum β = -0.65 [95% CI -0.25, -1.07]), driven mainly by Zn and Pb. Conclusion: The CC may demonstrate a postnatal critical window to metals, with higher exposure to Zn and Pb associated with reduced FA. These results may help understand the role of exposure timing in driving neurodevelopmental outcomes, pointing to future optimal and timely public health interventions.

Biomarkers of maternal lead exposure during pregnancy using micro-spatial child deciduous dentine measurements

BackgroundLead is a toxic chemical of public health concern, however limited biomarkers are able to reconstruct prior lead exposures in early-life when biospecimens are not collected and stored. Although child tooth dentine measurements accurately assess past child perinatal lead exposure, it has not been established if they reflect maternal exposure in pregnancy. AimTo assess the prenatal relationship between child tooth dentine and maternal blood lead measurements and to estimate maternal lead exposure during the 2nd and 3rd trimesters of pregnancy from weekly child dentine profiles. MethodsWe measured early-life lead exposure in child tooth dentine and maternal blood from 419 child-mother dyads enrolled in the Programming Research in Obesity, Growth, Environment and Social Stress (PROGRESS) cohort. We employed the Super-Learner algorithm to determine the relationship of dentine lead data with maternal blood lead concentrations and to predict maternal lead from child dentine lead data in blinded analyses. We validated and quantified the bias of our results internally. ResultsMothers had moderate blood lead levels (trimesters: 2nd = 29.45 ug/L, 3rd = 31.78 ug/L). Trimester-averaged and weekly child dentine lead measurements were highly correlated with maternal blood levels in the corresponding trimesters. The predicted trimester-specific maternal lead levels were significantly correlated with actual measured blood values (trimesters: 2nd = 0.83; 3rd = 0.88). Biomarkers of maternal lead exposure discriminated women highly exposed to lead (>mean) with 85 % and 96 % specificity in the 2nd and 3rd trimesters, respectively, with 80 % sensitivity. DiscussionWeekly child dentine lead levels can serve as biomarkers of past child and maternal lead exposures during pregnancy.

Prenatal and early childhood critical windows for the association of nephrotoxic metal and metalloid mixtures with kidney function.

As renal development and maturation processes begin in utero and continue through early childhood, sensitive developmental periods arise during which metal exposures can program subclinical nephrotoxicity that manifests later in life. We used novel dentine biomarkers of established nephrotoxicants including arsenic (As), cadmium (Cd), lead (Pb), chromium (Cr), and lithium (Li), and their mixtures, to identify critical windows of exposure-associated kidney function alterations in preadolescents. Participants included 353 children in the Programming Research in Obesity Growth, Environment and Social Stressors (PROGRESS) longitudinal birth cohort study based in Mexico City. Estimated glomerular filtration rate (eGFR) was assessed in 8-12 year old children using serum cystatin C measures. Pre- and postnatal metal(loid) concentrations were assessed in weekly increments by analyzing deciduous teeth with laser ablation-inductively coupled plasma-mass spectrometry. We used reverse distributed lag models (rDLMs) and lagged Weighted Quantile Sum (L-WQS) regression to examine time-varying associations between weekly perinatal metal(loid) exposure or metal(loid) mixtures and preadolescent eGFR while adjusting for age, sex, BMI z-score, SES and prenatal tobacco smoke exposure. We identified a critical window of susceptibility to Pb exposure, in the late 3rd trimester (5 weeks prior to birth) during which higher Pb exposure was associated with children's increased eGFR. When all elements were assessed as a mixture, we identified late 2nd/early 3rd trimester (weeks 8-17 of gestation) as a window of vulnerability associated with decreased eGFR, with Li and Cr contributing the greatest weights to the association. When stratified by sex, we observed stronger effects among boys than girls. Using tooth-matrix biomarkers, we identified discrete developmental exposure windows wherein Pb and metal(loid) mixtures were associated with altered preadolescent kidney function.

Intermediate- and long-term associations between air pollution and ambient temperature and glycated hemoglobin levels in women of child bearing age.

Background:Air pollution has been linked to obesity while higher ambient temperatures typically reduce metabolic demand in a compensatory manner. Both relationships may impact glucose metabolism, thus we examined the association between intermediate- and long-term exposure to fine particulate matter (PM2.5) and ambient temperature and glycated hemoglobin (HbA1c), a longer-term marker of glucose control.Methods:We assessed 3-month, 6-month, and 12-month average air pollution and ambient temperature at 1-km2 spatial resolution via satellite remote sensing models (2013–2019), and assessed HbA1c at four, six, and eight years postpartum in women enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort based in Mexico City. PM2.5 and ambient temperature were matched to participants’ addresses and confirmed by GPS tracker. Using linear mixed-effects models, we examined the association between 3-month, 6-month, and 12-month average PM2.5 and ambient temperature with repeated log-transformed HbA1c values. All models included a random intercept for each woman and were adjusted for calendar year, season, and individual-level confounders (age, marital status, smoking, alcohol consumption level, and education level).Results:We analyzed 1,265 HbA1c measurements of 484 women. Per 1 μg/m3 increase in 3-month and 6-month PM2.5, HbA1c levels increased by 0.28% (95% confidence interval (95 %CI): 0.14, 0.42%) and 0.28% (95 %CI: 0.04, 0.52%) respectively. No association was seen for 12-month average PM2.5. Per 1 °C increase in ambient temperature, HbA1c levels decreased by 0.63% (95 %CI: −1.06, −0.21%) and 0.61% (95 %CI: −1.08, −0.13%), while the 12-month average again is not associated with HbA1c.Conclusions:Intermediate-term exposure to PM2.5 and ambient temperature are associated with opposing changes in HbA1c levels, in this region of high PM2.5 and moderate temperature fluctuation. These effects, measurable in mid-adult life, may portend future risk of type 2 diabetes and possible heart disease.

Prenatal lead exposure, telomere length in cord blood, and DNA methylation age in the PROGRESS prenatal cohort

BackgroundLead is a ubiquitous pollutant with deleterious effects on human health and remains a major current public health concern in developing countries. This heavy metal may interfere with nucleic acids via oxidative stress or epigenetic changes that affect biological markers of aging, e.g., telomere length and DNA methylation (DNAm). Telomere shortening associates with biological age in newborns, and DNA methylation at specific CpG sites can be used to calculate “epigenetic clocks". ObjectiveThe aim of this study was to examine the associations of prenatal lead exposures with telomere length and DNA-methylation-based predictors of age in cord blood. DesignThe study included 507 mother–child pairs from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a birth cohort in Mexico City. Maternal blood (second trimester, third trimester and at delivery) and bone lead levels (one month postpartum) were measured using inductively coupled plasma-mass spectrometry and X-ray fluorescence, respectively. Cord blood leukocyte telomere length was measured using quantitative PCR and apparent age by DNA methylation biomarkers, i.e., Horvath's DNA methylation age and the Knight's predictor of gestational age. ResultsAverage maternal age was 28.5 ± 5.5 years, and 51.5% reported low socioeconomic status. Children's mean telomere length was 1.2 ± 1.3 relative units, and mean DNA methylation ages using the Horvath's and Knight's clocks were −2.6 ± 0.1 years and 37.9 ± 1.4 weeks (mean ± SD), respectively. No significant associations were found between maternal blood and bone lead concentrations with telomere length and DNAm age in newborns. ConclusionWe found no associations of prenatal lead exposure with telomere length and DNA methylation age biomarkers.

Association between prenatal metal exposure and adverse respiratory symptoms in childhood

IntroductionManganese and lead have been cross-sectionally associated with adverse respiratory outcomes in childhood but there is limited data on their combined effects starting in utero. We examined associations between in utero exposure to metals and childhood respiratory symptoms. MethodsWe assessed 633 mother-child dyads enrolled in the Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) birth cohort in Mexico City. Blood manganese (BMn) and lead (BPb) were measured in mothers at 2nd and 3rd trimester. Ever wheeze, current wheeze and asthma diagnosis were ascertained at 4–5 and 6–7 year visits through the International Study of Asthma and Allergies in Childhood survey. Logistic mixed model regression was used to assess the association between prenatal metals and respiratory outcomes in children across the 4–5 and 6–7 year visits. Covariates included mother's age, education and asthma, environmental tobacco smoke, child's sex and assessment time. ResultsIn adjusted models, higher 2nd trimester BPb had a significant association with elevated odds of ever wheeze (Odds Ratio (OR): 1.97, 95% CI: 1.05, 3.67). BMn at 2nd trimester was associated with decreased (OR: 0.06, 95% CI: 0.01, 0.35) odds of current wheeze. We did not find any statistically significant associations with 3rd trimester blood metals. ConclusionPrenatal exposure to Pb was associated with higher odds of ever wheeze while Mn was negatively associated with odds of current wheeze. These findings underscore the need to consider prenatal metal exposure, including low exposure levels, in the study of adverse respiratory outcomes.

Prenatal metal mixture concentrations and reward motivation in children

Reward motivation is a complex umbrella term encompassing the cognitions, emotions, and behaviors involved in the activation, execution, and persistence of goal-directed behavior. Altered reward motivation in children is characteristic of many neurodevelopmental and psychiatric disorders. Previously difficult to operationalize, the Progressive Ratio (PR) task has been widely used to assess reward motivation in animal and human studies, including children. Because the neural circuitry supporting reward motivation starts developing during pregnancy, and is sensitive to disruption by environmental toxicants, including metals, the goal of this study was to examine the association between prenatal concentrations of a mixture of neurotoxic metals and reward motivation in children. We measured reward motivation by administering a PR test to 373 children ages 6–8 years enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) Study in Mexico City. Children were asked to press a response lever for a token reward; one press on the response lever was required to earn the first token and each subsequent token required an additional 10 lever presses. Maternal blood concentrations of lead, manganese, zinc, arsenic, cadmium, and selenium were measured using inductively-coupled plasma mass spectrometry during the 2nd and 3rd trimesters of pregnancy. We performed generalized Weighted Quantile Sum (gWQS) regression analyses to examine associations between the prenatal metal mixture and reward motivation; adjusting for child sex, birthweight and age; and maternal IQ, education, and socioeconomic status. The prenatal metal mixture was significantly associated with higher motivation as indicated by more lever presses (ß = 0.02, p < 0.001) and a shorter time between receiving the reinforcer and the first press (ß = 0.23, p = 0.01), and between subsequent presses (ß = 0.07, p = 0.005). Contributions of different metals to this association differed by trimester and child sex. These findings suggest that children with increased exposure to metal during the 2nd and 3rd trimesters of gestation demonstrate increased reward motivation, which may reflect a tendency to perseverate or hypersensitivity to positive reinforcement.

Prenatal and Early Childhood Exposure to Lead and Repeated Measures of Metabolic Syndrome Risk Indicators From Childhood to Preadolescence

Background: Exposure to lead (Pb) during the early life stages has been associated with the development of metabolic syndrome (MetS). Longitudinal studies of Pb exposure in critical developmental windows in children are limited.Methods: Our study included 601 mother–child dyads from the PROGRESS (Programming Research in Obesity, Growth, Environment and Social Stressors) birth cohort. Blood lead levels (BLLs) were assessed during the second and third gestational trimesters, in cord blood at delivery, and at ages 1, 2, and 4 years. Bone lead levels in the patella and tibia were assessed at 1 month postpartum and evaluated in separate models. To account for cumulative exposure (prenatal, postnatal, and cumulative), we dichotomized the BLLs at each stage visit and determined the following: “higher” if a BLL was at least once above the median (HPb) and “lower” if all BLLs were below the median (LPb). We analyzed fasting glucose, HbA1c, triglycerides (TGs), total cholesterol (TC), high-density lipoprotein cholesterol (cHDL), low-density lipoprotein cholesterol (cLDL), body mass index, waist circumference (WC), body fat percentage, and systolic (SBP) and diastolic blood pressure (DBP) at two study visits between 6 and 12 years of age and created cutoff points based on the clinical guidelines for each indicator. Mixed effects models were used to analyze each outcome longitudinally for each BLL score, adjusting for child's sex, size for gestational age, child's age, maternal parity, mother's age, and socioeconomic status.Results: We observed associations for HPb exposure and TC in all stages (OR = 0.53, 95%CI = 0.32–0.86) and postnatally (OR = 0.59, 95%CI = 0.36–0.94) and for prenatal HPb and TGs (OR = 0.65, 95%CI = 0.44–0.95). HPb at all stages was associated with WC (OR = 0.27, 95%CI = 0.08–0.86), BMI (OR = 0.33, 95%CI = 0.11–0.99), SBP (OR = 0.53, 95%CI = 0.32–0.85), and DBP (OR = 0.57, 95%CI = 0.34–0.95). Pb levels in the patella were associated with cHDL (OR = 1.03, 95%CI = 1.00–1.07) and those in the tibia with TGs (OR = 0.95, 95%CI = 0.91–0.99).Conclusion: Early life exposure to Pb may alter early indicators of MetS. A follow-up of these children will allow for more definition on the impact of longer-term exposures.

Impact of paternal education on epigenetic ageing in adolescence and mid-adulthood: a multi-cohort study in the USA and Mexico.

Both parental and neighbourhood socio-economic status (SES) are linked to poorer health independently of personal SES measures, but the biological mechanisms are unclear. Our objective was to examine these influences via epigenetic age acceleration (EAA)-the discrepancy between chronological and epigenetic ages. We examined three USA-based [Coronary Artery Risk Disease in Adults (CARDIA) study, Fragile Families and Child Wellbeing Study (FFCWS) and Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS)] and one Mexico-based (Project Viva) cohort. DNA methylation was measured using Illumina arrays, personal/parental SES by questionnaire and neighbourhood disadvantage from geocoded address. In CARDIA, we examined the most strongly associated personal, parental and neighbourhood SES measures with EAA (Hannum's method) at study years 15 and 20 separately and combined using a generalized estimating equation (GEE) and compared with other EAA measures (Horvath's EAA, PhenoAge and GrimAge calculators, and DunedinPoAm). EAA was associated with paternal education in CARDIA [GEEs: βsome college = -1.01 years (-1.91, -0.11) and β<high school = 1.05 (0.09, 2.01) vs college graduates] and FFCWS [GEEs: β<high school = 0.62 (0.00, 1.24)]. We found stronger associations for some paternal education categories among White adults (for GEE, βsome college = -1.39 (-2.41, -0.38)], men (βsome college = -1.76 (-3.16, -0.35)] and women [β<high school = 1.77 (0.42, 3.11)]. These findings suggest that EAA captures epigenetic impacts of paternal education independently of personal SES later in life. Longitudinal studies should explore these associations at different life stages and link them to health outcomes. EAA could be a useful biomarker of SES-associated health and provide important insight into the pathogenesis and prevention of chronic disease.

Changes in depression symptoms in Mexican women during the COVID-19 pandemic

BACKGROUND AND AIM: While COVID-19 infection affects health directly, the pandemic response has widespread implications as physical and social environments were radically changed by social distancing and stay at home measures. Mental health effects are important effects to track. We aimed to examine changes in depression and stress levels before and during the COVID-19 pandemic in women from a longitudinal cohort based in Mexico City. METHODS: We studied 471 women enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, who completed the Edinburgh Depression Scale (EDS) prior to the pandemic (2018-2019) and during the pandemic (May-November 2020). Change in EDS score between the two time periods was calculated. New onset depression was defined an EDS score 12 only in the pandemic period. Psychosocial stress for both time periods was ascertained through endorsement of negative life events across 11 domains using the CRISYS questionnaire. Associations between stress at both time periods and depression were analyzed in generalized linear models adjusting for age, socio-economic status and family social support. RESULTS:Higher stress (median) during the pandemic, but not prior to it, was associated with an increase in depression score (β: 2.22; 95%CI [1.15, 3.28]), and higher odds of new onset depression (OR: 1.25; 95% CI [1.01, 1.55]). Higher stress during the pandemic in particular domains, including personal relationships (β: 1.82 [95%CI: 0. 84, 2.80], home (β:1.41; [95%CI 0.22, 2.60]) and financial (β: 1.72; [95%CI: 0.71, 2.73]) were associated with an increase in depression score. We did not find significant differences in the distribution of depression or stress scores pre and during pandemic. CONCLUSIONS:High levels of stress during the pandemic were associated with increases in depression scores and new onset depression. Future studies should examine the long-term effects of stress associated with the pandemic on mental and overall health. KEYWORDS: mental health outcomes, female, covid-19, epidemiology

Early life critical windows of metal exposure associated with whole brain white matter changes in children

BACKGROUND AND AIM: The brain white matter (WM) connects gray matter regions into functional networks and is critical for human cognition and behavior. Early-life exposure to metals may impact fetal WM development. Most environmental studies consider single exposures, potentially missing the combined effects of mixtures. In addition, the developmental timing of exposure may be as important as the dose. Little is known about critical windows to nutritive and toxicant metal mixtures on the developing brain. In this study, we investigated associations between early life exposure to a mixture of metals and whole brain white matter in children. METHODS: In preliminary analysis of 30 subjects (6-10 years; 19 females) enrolled in a neuroimaging follow-up visit of the ongoing Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, we estimated weekly early life exposure (12th gestation week through one year of age) to 10 nutritive and toxicant metals (Mn, Zn, Pb, Mg, Li, Ca, Cr, Cu, Sr, Ba) in deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. Whole brain WM microstructure integrity was estimated using fractional anisotropy (FA) from diffusion tensor imaging (DTI) acquired in a 3T Siemens scanner. We used lagged weighted quantile sum (lWQS) regression to estimate a time-varying mixture effect of multiple metals on whole brain FA. Models were adjusted for age. RESULTS:We observe a potential critical window to metal exposure during the postnatal period (0 - 13 weeks) showing positive association with whole brain FA. This association is driven mainly by Li, Mg, and Ca. Negative associations were not detected. CONCLUSIONS:WM microstructure integrity may demonstrate a postnatal critical window to essential elements. These results may help understand the role of exposure timing in driving neurodevelopmental effects, thereby pointing to future optimal, efficient, and properly timed public health interventions. KEYWORDS: Neurodevelopmental outcomes, Mixtures analysis, Mixtures

Health Effects from Urban Stress in Women in Mexico City

BACKGROUND AND AIM: Individuals in urban neighborhoods often face disproportionately higher levels of environmental and social stressors; however, the health effects from urban stressors remains poorly understood. We studied the association between urban stress and symptoms of depression, fatigue, and sleep disruption in a cohort of women in Mexico City. METHODS: Participants included 343 women from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) birth cohort in Mexico City. Women were administered the urban stress scale, where they were asked to rate their annoyance on select urban situations that city-dwellers face, such as unhealthy air, traffic, noise, lack of green space, and aggression. Six different constructs were summarized to create an overall continuous index and this was dichotomized at the median. Symptoms of depression were assessed at the same study visit using the Edinburgh Depression Scale; the NIH toolbox was used to assess fatigue and sleep disruption. Linear regression models were used to estimate the association with continuous symptoms comparing women with high urban stress to those with lower levels. Models were adjusted for socioeconomic status, education, age, body mass index, and social support. RESULTS:High urban stress was associated with higher depressive symptoms (β: 1.50; 95% CI: 0.34, 2.65), fatigue (β: 2.18; 95% CI: 0.65, 3.71), and sleep disruption (β: 2.01; 95% CI: 0.45, 3.58). Associations were strongest among women who were highly annoyed by environmental concerns, including unhealthy air and lack of green space. CONCLUSIONS:Urban stress plays an important role in women’s psychological and physical health, highlighting the importance of including these measures in environmental health studies in urban settings. KEYWORDS: built environment, environmental justice, female, mental health outcomes, socio-economic factors, non-chemical stressors

Associations between air pollution and temperature on glycated hemoglobin levels in women of child bearing age

BACKGROUND AND AIM: Fine particulate matter (PM₂.₅) is associated with cardiovascular disease possibly through impaired glucose metabolism. Higher temperature has been linked to lower blood glucose levels in clinical settings as well. We examined the association between intermediate-term exposure to PM₂.₅ and temperature and glycated hemoglobin (HbA1c), a longer-term marker of glucose control. METHODS: We assessed air pollution and temperature at 1-km² spatial resolution via satellite-based models, and HbA1c four years postpartum in women enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort in Mexico City (2013–2019). PM₂.₅ and temperature were matched to participants’ addresses and confirmed by GPS tracker. Using linear mixed-effects models, we examined the association between 3-month and 6-month average PM₂.₅ and temperature with log-transformed HbA1c values. Both models included a random intercept per woman and were adjusted for calendar year, season, and individual-level confounders (age, marital status, smoking status, alcohol consumption level, and education level). RESULTS:We analyzed 1,257 tests of 490 women. PM₂.₅ ranged from 3.2µg/m³ to 76.7µg/m³, average temperature ranged from 6.4°C to 22.9°C, and HbA1c values ranged from 3.0% to 12.8%. Results were antilog transformed and are presented as percent increases in HbA1c levels. Per interquartile increase in 3-month and 6-month average PM₂.₅, HbA1c levels increased by 1.85% (95%CI: 0.92, 2.80) and 1.08% (95%CI: 0.10%, 2.08%) respectively. Per one-degree Celsius increase in temperature, HbA1c levels decreased by 0.64% (95%CI: -1.05%, -0.23%) and 0.58% (95%CI: -1.04%, -0.12%) respectively. CONCLUSIONS:Intermediate-term exposure to PM₂.₅ and temperature are associated with opposing changes in HbA1c levels, in this region of high PM₂.₅ and moderate temperature fluctuation. These effects, measurable in mid-adult life, may portend future risk of heart disease and type 2 diabetes. Additional research is necessary to elucidate whether the observed associations with HbA1c mediate early indicators of cardiovascular disease as the cohort ages. KEYWORDS: air pollution, particulate matter, temperature, diabetes, glycated hemoglobin, HbA1c

Association between prenatal metal exposure and respiratory symptoms in childhood

BACKGROUND AND AIM: Arsenic, manganese, and lead have been cross-sectionally associated with adverse respiratory outcomes in childhood but there is limited data on their combined effects starting in utero. Our aim was to examine associations between prenatal lead, arsenic, and manganese exposure and respiratory symptoms in childhood. METHODS: We assessed 637 mother-child dyads enrolled in the Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) birth cohort in Mexico City. Blood manganese (BMn), arsenic (BAs), and lead (BPb) were measured in mothers at 2nd trimester. Ever wheeze, current wheeze and asthma diagnosis was based on the caregiver’s answers (yes/no) from the International Study of Asthma and Allergies in Childhood (ISAAC) survey applied at 4-5 and 6-7 years old. Covariates included maternal education, maternal asthma status, maternal age at enrollment, child’s sex, and prenatal environmental tobacco smoke exposure. A logistic mixed model regression was generated to simultaneously assess the association between prenatal metals and ever wheeze, current wheeze, and asthma diagnosis longitudinally across both the 4-5 and 6-7 year study visits. RESULTS:The mean ± standard deviation for log-transformed BMn, BPb, and BAs at 2nd trimester were 0.14 µg/dL ± 0.15, 0.48 µg/dL ± 0.27, and -1.11 µg/dL ± 0.19, respectively. In the adjusted model, BPb (Odds Ratio (OR): 1.95, 95% CI: 1.04-3.66) and BAs (OR: 3.44, 95% CI: 1.05-11.34) at 2nd trimester were associated with increased odds of ever wheeze and current wheeze, respectively. BMn at 2nd trimester (OR: 0.05, 95% CI: 0.01-0.27) was negatively associated with current wheeze. CONCLUSIONS:Prenatal exposure to arsenic and lead was associated with higher odds of ever and current wheeze while manganese was negatively associated with odds of current wheeze in childhood. These findings underscore the need to consider prenatal metal exposure, including low levels of exposure, in the study of respiratory diseases. KEYWORDS: Respiratory outcomes, Heavy metals, Allergies, Asthma, Children's environmental health