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Background: Childhood exposure to air pollution has been linked with maladaptive cognitive development; however, less is known about the association between prenatal fine particulate matter (PM 2.5 ) exposure and childhood behavior., Objectives: Our aim was to assess the association between prenatal PM 2.5 exposure and behavioral development in 4-6 year old children residing in Mexico City., Methods: We used data from 539 mother-child pairs enrolled in a prospective birth cohort in Mexico City. We estimated daily PM 2.5 exposure using a 1 km 2 satellite-based exposure model and averaged over each trimester of pregnancy. We assessed childhood behavior at 4-6 years of age using the parent-completed Behavioral Assessment Scale for Children (BASC-2) composite scores and subscales. We used linear regression models to estimate change in BASC-2 T-scores with trimester specific 5-μg/m 3 increases in PM 2.5 . All models were mutually adjusted for PM 2.5 exposures during the other trimesters, maternal factors including age, education, socioeconomic status, depression, and IQ, child's age at study visit, and season. We additionally assessed sex-specific effects by including an interaction term between PM 2.5 and sex., Results: Higher first trimester PM 2.5 exposure was associated with reduced Adaptive Skills scores (β: -1.45, 95% CI: -2.60, -0.30). Lower scores on the Adaptive Skills composite score and subscales indicate poorer functioning. For PM 2.5 exposure during the first trimester, decrements were consistent across adaptive subscale scores including Adaptability (β: -1.51, 95% CI: -2.72, -0.30), Social Skills (β: -1.63, 95% CI: -2.90, -0.36), and Functional Communication (β: -1.21, 95% CI: -2.21, -0.21). The association between 1 st trimester PM 2.5 and depression was stronger in males than females (β for males: 1.52, 95% CI: -0.41, 3.45; β for females: -0.13, 95% CI: -1.99, 1.72; p-int: 0.07)., Conclusions: Exposure to PM 2.5 during early pregnancy may be associated with impaired behavioral development in children, particularly for measures of adaptive skills. These results suggest that air pollution impacts behavioral domains as well as cognition, and that the timing of exposure may be critical., (Copyright © 2020. Published by Elsevier B.V.)

In utero phthalate exposure has been associated with neurodevelopmental disorders, nevertheless, trimester-specific susceptibility remains understudied. Our aim was to identify susceptible windows to the effects of gestational High-Molecular-Weight Phthalates (HMWP) exposure on 48 months' neurodevelopment. We measured six HMWP metabolites (MEHP, MEHHP, MEOHP, MECPP, MBzP and MCPP) in urine samples collected during each trimester from women in the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort ( n = 218). We assessed children's motor (MS), cognitive (GCI) and memory (MeS) abilities using McCarthy Scales of Children's Abilities (MSCA). We used linear regression models to examine associations between trimester-specific phthalate metabolites and MSCA scores, adjusted for sex, gestational age, breastfeeding, and maternal IQ. Although phthalate concentrations were similar across trimesters, first and second trimester phthalates were inversely associated with MS and GCI, with first trimester associations with MS being the strongest and statistically significant. Stronger associations were seen with MS and GCI among boys compared to girls, however interaction terms were not statistically significant. Our results suggest that early gestation is a sensitive window of exposure to HMWP for neurodevelopment, particularly in boys. Regulations on phthalate content in food as well as pregnancy consumption guidelines are necessary to protect future generations.

Background: Exposure to air pollution is associated with increased blood pressure (BP) in adults and children. Some evidence suggests that air pollution exposure during the prenatal period may contribute to adverse cardiorenal health later in life. Here we apply a distributed lag model (DLM) approach to identify critical windows that may underlie the association between prenatal particulate matter ≤ 2.5 μm in diameter (PM 2.5 ) exposure and children's BP at ages 4-6 years., Methods: Participants included 537 mother-child dyads enrolled in the Programming Research in Obesity, GRowth Environment, and Social Stress (PROGRESS) longitudinal birth cohort study based in Mexico City. Prenatal daily PM 2.5 exposure was estimated using a validated satellite-based spatio-temporal model and BP was measured using the automated Spacelabs system with a sized cuff. We used distributed lag models (DLMs) to examine associations between daily PM 2.5 exposure and systolic and diastolic BP (SBP and DBP), adjusting for child's age, sex and BMI, as well as maternal education, preeclampsia and indoor smoking report during the second and third trimester, seasonality and average postnatal year 1 PM 2.5 exposure., Results: We found that PM 2.5 exposure between weeks 11-32 of gestation (days 80-226) was significantly associated with children's increased SBP. Similarly, PM 2.5 exposure between weeks 9-25 of gestation (days 63-176) was significantly associated with increased DBP. To place this into context, a constant 10 μg/m 3 increase in PM 2.5 sustained throughout this critical window would predict a cumulative increase of 2.6 mmHg (CI: 0.5, 4.6) in SBP and 0.88 mmHg (CI: 0.1, 1.6) in DBP at ages 4-6 years. In a stratified analysis by sex, this association persisted in boys but not in girls., Conclusions: Second and third trimester PM 2.5 exposure may increase children's BP in early life. Further work investigating PM 2.5 exposure with BP trajectories later in childhood will be important to understanding cardiorenal trajectories that may predict adult disease. Our results underscore the importance of reducing air pollution exposure among susceptible populations, including pregnant women., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Humans are exposed to mixtures of chemicals across their lifetimes, a concept sometimes called the "exposome." Mixtures likely have temporal "critical windows" of susceptibility like single agents and measuring them repeatedly might help to define such windows. Common approaches to evaluate the effects of chemical mixtures have focused on their effects at a single time point. Our goal is to expand upon these previous techniques and examine the time-varying critical windows for metal mixtures on subsequent neurobehavior in children., Methods: We propose two methods, joint weighted quantile sum regression (JWQS) and meta-weighted quantile sum regression (MWQS), to estimate the effects of chemical mixtures measured across multiple time points, while providing data on their critical windows of exposure. We compare the performance of both methods using simulations. We also applied both techniques to assess second and third trimester metal mixture effects in predicting performance in the Rapid Visual Processing (RVP) task from the Cambridge Neuropsychological Test Automated Battery (CANTAB) assessed at 6-9 years in children who are part of the PROGRESS (Programming Research in Obesity, GRowth, Environment and Social Stressors) longitudinal cohort study. The metals, arsenic, cadmium (Cd), cesium, chromium, lead (Pb) and antimony (Sb) were selected based on their toxicological profile., Results: In simulations, JWQS and MWQS had over 80% accuracy in classifying exposures as either strongly or weakly contributing to an association. In real data, both JWQS and MWQS consistently found that Pb and Cd exposure jointly predicted longer latency in the RVP and that second trimester exposure better predicted the results than the third trimester. Additionally, both JWQS and MWQS highlighted the strong association Cd and Sb had with lower accuracy in the RVP and that third trimester exposure was a better predictor than second trimester exposure., Conclusions: Our results indicate that metal mixtures effects vary across time, have distinct critical windows and that both JWQS and MWQS can determine longitudinal mixture effects including the cumulative contribution of each exposure and critical windows of effect.

Background: Prenatal and early childhood lead exposures have been associated with reduced weight in infants and young children, while studies that have examined such associations in children during peripubescence are rare., Objectives: We investigated the associations of prenatal and early-life exposure to lead with indices of adiposity in peripubertal children living in Mexico City., Methods: Maternal bone lead (as a proxy for cumulative fetal exposure) was assessed at 1 month postpartum. Blood samples were obtained from children annually from 1 to 4 years. Multivariable linear regression models were used to examine the association between each lead biomarker and BMI z-score, waist circumference, sum of skinfolds and body fat percentage in 248 children aged 8-16 years., Results: After adjusting for covariates, maternal patella lead was associated with lower child BMI z-score (β = -0.02, 95% CI: 0.03, -0.01, p = 0.004), waist circumference (β = -0.12 cm, 95% CI: 0.22, -0.03, p = 0.01), sum of skinfolds (β = -0.29 mm, 95% CI: 0.50, -0.08, p = 0.007) and body fat percentage (β = -0.09%, 95% CI: 0.17, -0.01, p = 0.03). No significant associations were detected from the postnatal exposure period., Conclusions: We observed a significant and inverse association of prenatal lead exposure with body composition in Mexican children, suggesting the potential role of early lead exposure in the fetal programming of child growth. Further research on the biological mechanisms underlying these associations is needed., (Copyright © 2019. Published by Elsevier GmbH.)

Introduction: Lead (Pb) crosses the placenta and can cause oxidative stress, reduced fetal growth and neurological problems. The principal source of oxidative stress in human cells is mitochondria. Therefore, disruption of normal mitochondrial function during pregnancy may represent a primary mechanism behind the adverse effects of lead. We sought to assess the association of Pb exposure during pregnancy with mitochondrial DNA (mtDNA) content, a sensitive marker of mitochondrial function, in cord blood., Materials and Methods: This study comprised mother-infant pairs from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a prospective birth-cohort that enrolled 1050 pregnant women from Mexico City who were receiving prenatal care between December 2007 and July 2011. Quantitative PCR was used to calculate relative MtDNA content (mitochondrial-to-nuclear DNA ratio (mtDNA/nDNA)) in cord blood. Lead concentrations in both maternal blood (2nd and 3rd trimester and at delivery day) and in cord blood were measured by ICP-MS. Multivariable regression models adjusting for multiple confounders were fitted with 410 mother-infant pairs for whom complete data for mtDNA content, lead levels, and covariates were available., Results: Maternal blood Pb measured in the second (mean 3.79 μg/dL, SD 2.63; β = 0.059, 95% CI 0.008, 0.111) and third trimester (mean 3.90 μg/dL; SD 2.84; β = 0.054, 95% CI 0.002, 0.107) during pregnancy and PB in cord blood (mean 3.50 μg/dL, SD 2.59; β = 0.050, 95% CI 0.004; 0.096) were associated with increased cord blood mtDNA content (mean 1.46, SD 0.44). In two-way interaction analyses, cord blood Pb marginally interacted with gestational age leading to an increase in mtDNA content for pre-term births (Benjamini-Hochberg False Discovery Rate correction; BH-FDR = 0.08)., Conclusion: This study shows that lead exposure in pregnancy alters mtDNA content in cord blood; therefore, alteration of mtDNA content might be a mechanism underlying the toxicity of lead., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The programming of sleep architecture begins in pregnancy and depends upon optimal in utero formation and maturation of the neural connectivity of the brain. Particulate air pollution exposure can disrupt fetal brain development but associations between fine particulate matter (PM 2.5 ) exposure during pregnancy and child sleep outcomes have not been previously explored., Methods: Analyses included 397 mother-child pairs enrolled in a pregnancy cohort in Mexico City. Daily ambient prenatal PM 2.5 exposure was estimated using a validated satellite-based spatio-temporally resolved prediction model. Child sleep periods were estimated objectively using wrist-worn, continuous actigraphy over a 1-week period at age 4-5 years. Data-driven advanced statistical methods (distributed lag models (DLMs)) were employed to identify sensitive windows whereby PM 2.5 exposure during gestation was significantly associated with changes in sleep duration or efficiency. Models were adjusted for maternal education, season, child's age, sex, and BMI z-score., Results: Mother's average age was 27.7 years, with 59% having at least a high school education. Children slept an average of 7.7 h at night, with mean 80.1% efficiency. The adjusted DLM identified windows of PM 2.5 exposure between 31 and 35 weeks gestation that were significantly associated with decreased sleep duration in children. In addition, increased PM 2.5 during weeks 1-8 was associated with decreased sleep efficiency. In other exposure windows (weeks 39-40), PM 2.5 was associated with increased sleep duration., Conclusion: Prenatal PM 2.5 exposure is associated with altered sleep in preschool-aged children in Mexico City. Pollutant exposure during sensitive windows of pregnancy may have critical influence upon sleep programming., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Child neurodevelopment has been positively linked to maternal intake of polyunsaturated fatty acids (PUFAs) during pregnancy; however, it is unknown if that relationship persists among populations exposed to environmental neurotoxicants., Objective: The aim of this work was to assess whether maternal dietary intake of PUFAs during pregnancy is positively associated with child neurodevelopment, whose mothers were environmentally exposed to 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT)., Methods: A prospective cohort study with 276 mother-child pairs was performed in Mexico. Neurodevelopment was assessed by Bayley Scales II from children age 1 to 30 months. Dietary PUFAs intake was estimated by Food Frequency Questionnaire at 1st and 3rd trimester of pregnancy. DDE (1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene, the main metabolite of DDT) maternal serum levels were determined by electron capture gas chromatography. Longitudinal multivariate linear mixed-effects analysis, which combines mental (MDI) and motor (PDI) Bayley scales in a single model, were performed., Results: Our results show that in a sample environmentally exposed to DDT, maternal ingestion of DPA during the first trimester of pregnancy was positively associated with MDI (β = 0.10, 95% CI 0.02, 0.18) in children from 1 to 30 months. Likewise, our results suggest that dietary ALA may be also related to MDI., Conclusion: DPA may benefit neurodevelopment even in populations exposed to DDT. Our results strengthen the importance of PUFAs intake during the prenatal period.

Background: Phthalates are known endocrine disruptors and peroxisome proliferator-activated receptor (PPAR) activators, potentially capable of promoting an obesogenic effect. Pregnant women are especially vulnerable to phthalate exposure due to physiological and metabolic changes during pregnancy, including those related to the metabolism of xenobiotics. Phthalate exposure during pregnancy has been associated with early gestational weight gain, however, its effect on long-term weight gain remains unclear. The aim of the present study was to evaluate the association between phthalate exposure during pregnancy and long-term changes in weight among women., Methods: Urinary phthalate concentrations, socioeconomic, anthropometry and information on diet and socioeconomic status were collected during pregnancy from 178 women from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohort. Maternal body weight and diet information was also collected up to 5 times in the first year postpartum and twice during follow-up visits 5.2-10.7 years later. A path analysis was performed to assess associations between urinary phthalate metabolite levels during pregnancy and change in weight (kg) per year after delivery, including age, education, living with/without partner, parity, daily energy intake and breastfeeding duration., Results: The mean age at pregnancy was 27.3 ± 5.9 years and mean body mass index during the first postpartum year was 27.07 ± 4.22 kg/m 2 . On average, women gained 3.48 kg (0.52 ± 0.84 kg/year). A unit increase in log-transformed mono-3-carboxypropyl phthalate (MCPP) was associated with 0.33 kg (95% CI: 0.09, 0.56) higher weight gain per year, and mono-benzyl phthalate (MBzP) with 0.21 kg (95% CI: -0.38, -0.03) lower weight gain per year., Conclusion: Exposure to certain phthalates during pregnancy may be associated with long-term weight change in women. More studies on the effects of phthalate exposure during pregnancy on women's long-term health are required., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Maternal 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) serum levels during pregnancy have been negatively linked to child neurodevelopment in contrast to intake of omega-3 and -6 (ω-3 and ω-6) fatty acids., Objectives: To assess whether maternal dietary intake of ω-3 and ω-6 during pregnancy modifies the association between exposure to DDE and child neurodevelopment from age 42-60 months., Methods: Prospective cohort study with 142 mother-child pairs performed in Mexico. DDE serum levels were determined by electron capture gas chromatography. Dietary ω-3 and ω-6 intake was estimated by questionnaire. Child neurodevelopment was assessed by McCarthy Scales., Results: Docosahexaenoic (DHA) fatty acid intake significantly modified the association between DDE and motor component: increased maternal DDE was associated with lower motor development in children whose mothers had lower DHA intake (β log2DDE  = -1.25; 95% CI: -2.62, 0.12), in contrast to the non-significant increase among children whose mothers had higher DHA intake (β log2DDE-motor  = 0.50; 95% CI: 0.55, 1.56). Likewise, arachidonic fatty acid (ARA) intake modified the association between DDE and memory component: increased maternal DDE was associated with a significantly larger reduction in the memory component in children whose mothers had lower ARA intake (β log2DDE  = -1.31; 95% CI: -2.29, -0.32) than children whose mothers had higher ARA intake (β log2DDE-memory  = 0.17; 95% CI: -0.78, 1.11)., Conclusions: Dietary intake of DHA and ARA during pregnancy may protect against child neurodevelopment damage associated with prenatal maternal DDE levels., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Manganese (Mn) is an essential trace metal that is neurotoxic at high levels of exposure. Disruption of brain maturation processes during the prenatal period may have lasting consequences. During this critical period, the developing human brain is uniquely vulnerable to exposure to environmental toxicants such as Mn, and prenatal Mn exposure has been associated with changes in brain areas involved in emotion processing and regulation. The goal of the present pilot study was to examine whether prenatal Mn exposure is associated with changes in the intrinsic functional connectivity (iFC) of the brain in childhood, focusing on changes in emotional brain areas. We selected 15 subjects (age 6-7 years) from an ongoing longitudinal birth cohort study to participate in a resting state functional magnetic resonance imaging (fMRI) study. Prenatal Mn exposure was determined from maternal blood collected during the 2nd and 3rd trimesters of pregnancy. We used seed-based correlation analyses and independent component analyses to examine whether prenatal Mn exposure was associated with the iFC of the brain in children. We found that the right globus pallidus showed reduced iFC with the dorsal anterior cingulate cortex and lateral prefrontal cortex in children who were exposed to higher prenatal Mn levels, after controlling for sociodemographic confounders (SES, maternal education, child sex, home environment support) and environmental confounders (prenatal lead exposure and air pollution). These findings suggest that prenatal Mn exposure is associated with reduced iFC of brain areas involved in emotion processing and regulation in children. Future studies should investigate whether this reduced iFC mediates the association between prenatal Mn exposure and emotional dysfunction in childhood., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Normal prenatal neurodevelopment follows stages that are potentially influenced by both chemical and psychosocial environments. Exposure to elevated manganese during this critically vulnerable period has been found to be neurotoxic. Independently, maternal prenatal depression has been associated with subsequent neurodevelopmental decrements in children. The association between child neurodevelopment and prenatal co-exposure to manganese and maternal depression has not been sufficiently studied., Methods: During pregnancy and at birth, we measured maternal blood and cord blood manganese levels respectively. Maternal depression was assessed in the 3rd trimester of pregnancy using the Edinburgh Depression Scale. Neurodevelopment was evaluated at 24 months of age with the Bayley Scales of Infant Development. A multivariate multiple regression model was used to analyze cognitive, language and motor scores simultaneously for 473 children from the PROGRESS birth cohort in Mexico City., Results: Over 25% of our study participants reported having depressive symptoms. 3rd trimester blood manganese as well as depressive symptoms were independently negatively associated with all neurodevelopment scores in adjusted models. In stratified analyses, the negative association between manganese (maternal as well as cord blood) and 24-month language scores was stronger among women with depressive symptoms. Receptive language was mostly affected. Inverted U-shaped curves were seen for the association between with cord blood manganese and neurodevelopment scores., Conclusions: Our findings are in line with previous studies of manganese and depression neurotoxicity. The prenatal period may be particularly sensitive to manganese and depression co-exposures and should be of interest for public health interventions to promote healthy emotional and nutritional pregnancies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Some evidence suggests that fluoride may be neurotoxic to children. Few of the epidemiologic studies have been longitudinal, had individual measures of fluoride exposure, addressed the impact of prenatal exposures or involved more than 100 participants., Objective: Our aim was to estimate the association of prenatal exposure to fluoride with offspring neurocognitive development., Methods: We studied participants from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) project. An ion-selective electrode technique was used to measure fluoride in archived urine samples taken from mothers during pregnancy and from their children when 6-12 y old, adjusted for urinary creatinine and specific gravity, respectively. Child intelligence was measured by the General Cognitive Index (GCI) of the McCarthy Scales of Children's Abilities at age 4 and full scale intelligence quotient (IQ) from the Wechsler Abbreviated Scale of Intelligence (WASI) at age 6-12., Results: We had complete data on 299 mother-child pairs, of whom 287 and 211 had data for the GCI and IQ analyses, respectively. Mean (SD) values for urinary fluoride in all of the mothers (n=299) and children with available urine samples (n=211) were 0.90 (0.35) mg/L and 0.82 (0.38) mg/L, respectively. In multivariate models we found that an increase in maternal urine fluoride of 0.5mg/L (approximately the IQR) predicted 3.15 (95% CI: -5.42, -0.87) and 2.50 (95% CI -4.12, -0.59) lower offspring GCI and IQ scores, respectively., Conclusions: In this study, higher prenatal fluoride exposure, in the general range of exposures reported for other general population samples of pregnant women and nonpregnant adults, was associated with lower scores on tests of cognitive function in the offspring at age 4 and 6-12 y. https://doi.org/10.1289/EHP655.

Background: Air pollution exposure in childhood is associated with greater incidence and exacerbation of asthma, particularly in children whose parents report high levels of psychological stress. However, this interaction has not been completely elucidated in pregnancy., Objective: To examine whether the association between prenatal exposure to particulate matter no larger than 2.5 μm in diameter (PM 2.5 ) and wheeze in children is modified by prenatal stress., Methods: Mexican women were recruited during pregnancy (N = 552). Residential prenatal daily exposure to PM 2.5 was estimated using a satellite-based spatiotemporally resolved prediction model and averaged over trimesters. Maternal stress was indexed by maternal negative life events (NLE) score (range 0-11) ascertained during mid to late pregnancy. NLE scores were dichotomized at the median as low (NLE score ≤ 3) and high (NLE score > 3) stress. Reports of ever wheeze and wheeze in the past 12 months (current wheeze) for children were obtained using the International Study of Asthma and Allergies in Childhood survey at 48 months. The association between prenatal PM 2.5 and wheeze was analyzed using a modified Poisson regression and stratified by low vs high stress., Results: Greater PM 2.5 exposure during the first trimester was associated with increased risk of current wheeze among children with mothers reporting high prenatal stress (relative risk 1.35, 95% confidence interval 1.00-1.83, per interquartile range increase 3.8 μg/m 3 ) but not among those reporting low stress (relative risk 0.84, 95% confidence interval 0.61-1.16, per interquartile range increase 3.8 μg/m 3 ; P for interaction = .04)., Conclusion: Increased prenatal stress enhanced the association between PM 2.5 exposure in early pregnancy, and child wheeze at 48 months of age. It is important to consider chemical and nonchemical stressors together to more comprehensively characterize children's environmental risk., (Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: As population lead levels decrease, the toxic effects of lead may be distributed to more sensitive populations, such as infants with poor fetal growth., Objectives: To determine the association of prenatal lead exposure and fetal growth; and to evaluate whether infants with poor fetal growth are more susceptible to lead toxicity than those with normal fetal growth., Methods: We examined the association of second trimester maternal blood lead levels (BLL) with birthweight-for-gestational age (BWGA) z-score in 944 mother-infant participants of the PROGRESS cohort. We determined the association between maternal BLL and BWGA z-score by using both linear and quantile regression. We estimated odds ratios for small-for-gestational age (SGA) infants between maternal BLL quartiles using logistic regression. Maternal age, body mass index, socioeconomic status, parity, household smoking exposure, hemoglobin levels, and infant sex were included as confounders., Results: While linear regression showed a negative association between maternal BLL and BWGA z-score (β=-0.06 z-score units per log 2 BLL increase; 95% CI: -0.13, 0.003; P=0.06), quantile regression revealed larger magnitudes of this association in the <30th percentiles of BWGA z-score (β range [-0.08, -0.13] z-score units per log 2 BLL increase; all P values<0.05). Mothers in the highest BLL quartile had an odds ratio of 1.62 (95% CI: 0.99-2.65) for having a SGA infant compared to the lowest BLL quartile., Conclusions: While both linear and quantile regression showed a negative association between prenatal lead exposure and birthweight, quantile regression revealed that smaller infants may represent a more susceptible subpopulation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Lead and psychosocial stress disrupt similar but not completely overlapping mechanisms. Exposure during the prenatal period to each of these insults singularly has been found to alter normal neurodevelopment; however, longitudinal associations with stress modifying the effect of lead have not been sufficiently analyzed in epidemiologic studies., Objective: To evaluate prenatal stress as an effect modifier of gestational lead neurotoxicity., Methods: We used a structural equations modeling approach with a trivariate response to evaluate cognitive, language and motor scores of the Bayley Scales of Infant Development-III in 24month-old children (n=360). Maternal blood lead levels were measured at the 2nd and 3rd trimester and psychosocial stress during pregnancy was assessed using a negative life events (NLE) scale derived from the CRYSIS questionnaire., Results: 3rd trimester lead (mean 3.9±3.0 SDμg/dL) and stress (median=3 NLE) were negatively associated with Bayley III scores. Using the model's results we generated profiles for 0, 2, 4 and 6 NLE across lead levels (up to 10μg/dL) and observed a dose-response for the developmental scores when lead levels were below 2μg/dL. Each NLE curve had a different shape across increasing lead levels. Higher stress (NLE=6) resulted in lower cognitive scores for both sexes, in lower language scores in girls but not boys. In the absence of stress we saw a negative association with lead for all scores, however for language and motor scores, higher stress seemed to mask this association., Conclusions: Our work examined and confirmed prenatal stress exposure as a modifier of the well-known neurotoxic effects of prenatal lead. It adds to the existing evidence pointing at the importance of studying the co-exposure of chemical and non-chemical exposures, specifically of considering the emotional environment of children at early developmental stages of life., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Lead exposure during pregnancy remains a public health problem with potential lifelong impacts on children's growth and development. Mexico is unique in that stunting and obesity are both major public health concerns in children. This situation might be exacerbated by lead exposure which remains more common in Mexico than in the United States due in part to the use of lead glazed pottery in food preparation and storage. Our objective is to determine how lead exposure during pregnancy is associated with children's growth parameters, including height, weight, body mass index and percentage body fat measured between ages 4-6 years old in a Mexico City pregnancy cohort. Blood lead was collected in the 2nd and 3rd trimester of pregnancy as well as at delivery. Bone lead was assessed in mothers as a long term exposure biomarker. We performed multivariable linear regression analyses to assess the association between each of these lead exposure biomarkers and child anthropometry. We found a significant negative association between maternal 3rd trimester blood lead concentration and offspring height for age (β-0.10; 95% CI -0.19, -0.01), and a negative association between maternal 3rd trimester blood lead concentration and weight for age (β-0.11; 95% CI -0.22,-0.003). Our results in this Mexican population add to previous findings of an association of lead and decreased stature and weight in early childhood. Ongoing follow-up and longitudinal analyses may help elucidate how this impacts growth trajectory and other children's health outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Temperament is a psychological construct that reflects both personality and an infant's reaction to social stimuli. It can be assessed early in life and is stable over time Temperament predicts many later life behaviors and illnesses, including impulsivity, emotional regulation and obesity. Early life exposure to neurotoxicants often results in developmental deficits in attention, social function, and IQ, but environmental predictors of infant temperament are largely unknown. We propose that prenatal exposure to both chemical and non-chemical environmental toxicants impacts the development of temperament, which can itself be used as a marker of risk for maladaptive neurobehavior in later life. In this study, we assessed associations among prenatal and early life exposure to lead, mercury, poverty, maternal depression and toddler temperament., Methods: A prospective cohort of women living in the Mexico City area were followed longitudinally beginning in the second trimester of pregnancy. Prenatal exposure to lead (blood, bone), mercury, and maternal depression were assessed repeatedly and the Toddler Temperament Scale (TTS) was completed when the child was 24 months old. The association between each measure of prenatal exposure and performance on individual TTS subscales was evaluated by multivariable linear regression. Latent profile analysis was used to classify subjects by TTS performance. Multinomial regression models were used to estimate the prospective association between prenatal exposures and TTS performance., Results: 500 mother-child pairs completed the TTS and had complete data on exposures and covariates. Three latent profiles were identified and categorized as predominantly difficult, intermediate, or easy temperament. Prenatal exposure to maternal depression predicted increasing probability of difficult toddler temperament. Maternal bone lead, a marker of cumulative exposure, also predicted difficult temperament. Prenatal lead exposure modified this association, suggesting that joint exposure in pregnancy to both was most toxic., Conclusions: Maternal depression predicts difficult temperament and concurrent prenatal exposure to maternal depression and lead predicts a more difficult temperament phenotype in 2 year olds. The role of temperament as an intermediate variable in the path from prenatal exposures to neurobehavioral deficits and other health effects deserves further study.

Background: In recent years, pyrethroid pesticide use has increased in Mexico, the United States, and elsewhere, resulting in extensive human exposure. There is growing concern that pregnant women may be a particularly vulnerable population, as in utero fetal exposure during critical periods of development could adversely affect long-term neurobehavioral function., Methods: We measured maternal urinary 3-phenoxybenzoic acid (3-PBA) concentrations during the third trimester of pregnancy as a measure of in utero pyrethroid exposure to the fetus among participants in an established Mexico City birth cohort (n=187). In a subset of mothers, we measured 3-PBA during the first, second, and third trimester (n=21) to assess variability across pregnancy. We examined associations between third trimester 3-PBA concentrations and children's scores on the Mental Development Index (MDI) and Psychomotor Development Index (PDI) from the Bayley Scales for Infant Development (BSID-IIS) at 24 and 36 months of age., Results: 3-PBA was detected in 46% of all urine samples, with similar detection rates and geometric mean concentrations across pregnancy among the 21 participants who provided repeat samples. Participants in the medium and high 3-PBA categories (≥LOD) had lower MDI scores at 24 months compared to those in the low 3-PBA category (

Objective: We evaluated the effects of prenatal docosahexaenoic acid (DHA) supplementation on offspring development at 18 months of age., Design: Randomized placebo double-blind controlled trial., Settings: Cuernavaca, Mexico., Participants and Methods: We followed up offspring (n = 730; 75% of the birth cohort) of women in Mexico who participated in a trial of DHA supplementation during the latter half of pregnancy. We assessed the effect of the intervention on child development and the potential modifying effects of gravidity, gender, SES, and quality of the home environment., Interventions or Main Exposures: 400 mg/day of algal DHA., Outcome Measures: Child development at 18 months of age measured using the Spanish version of the Bayley Scales of Infant Development-II. We calculated standardized psychomotor and mental development indices, and behavior rating scale scores., Results: Intent-to-treat differences (DHA-control) were: Psychomotor Developmental Index -0.90 (95% CI: -2.35, 0.56), Mental Developmental Index -0.26 (95% CI: -1.63, 1.10) and Behavior Rating Scale -0.01 (95% CI: -0.95, 0.94). Prenatal DHA intake attenuated the positive association between home environment and psychomotor development index observed in the control group (p for interaction = 0.03) suggesting potential benefits for children living in home environments characterized by reduced caregiver interactions and opportunities for early childhood stimulation., Conclusions: Prenatal DHA supplementation in a population with low intakes of DHA had no effects on offspring development at 18 months of age although there may be some benefit for infants from poor quality home environments., Trial Registration: Clinicaltrials.gov NCT00646360.

Attention Deficit Hyperactivity Disorder (ADHD) is the most commonly diagnosed and studied cognitive and behavioral disorder in school-age children. The etiology of ADHD and ADHD-related behavior is unclear, but genetic and environmental factors, such as pesticides, have been hypothesized. The objective of this study was to investigate the relationship between in utero exposure to chlorpyrifos, chlorpyrifos-methyl, and/or 3,5,6-trichloro-2-pyridinol (TCPY) and ADHD in school-age Mexican children using TCPY as a biomarker of exposure. The temporal reliability of repeated maternal urinary TCPY concentrations across trimesters was also explored (N=21). To explore associations with ADHD-related outcomes in children, third trimester urinary TCPY concentrations in were measured in 187 mother-child pairs from a prospective birth cohort. Child neurodevelopment in children 6-11 years of age was assessed using Conners' Parental Rating Scales-Revised (CRS-R), Conners' Continuous Performance Test (CPT), and Behavior Assessment System for Children-2 (BASC-2). Multivariable linear regression models were used to test relationships for all children combined and also stratified by sex. Intraclass correlation coefficients (ICC) calculations were based on a random effects model. The ICC was 0.41 for uncorrected TCPY, and ranged from 0.29 to 0.32 for specific gravity-corrected TCPY. We did not observe any statistically significant associations between tertiles of maternal TCPY concentrations and ADHD-related outcomes in children. However, compared to the lowest tertile we found suggestive evidence for increased ADHD index in the highest TCPY tertile in boys (β=5.55 points; 95% CI (-0.19, 11.3); p=0.06) and increased attention problems for the middle tertile in girls (β=5.81 points; 95% CI (-0.75, 12.4); p=0.08). Considering the continued widespread agricultural and possible residential use of chlorpyrifos and chlorpyrifos-methyl in Mexico and the educational implications of cognitive and behavior deficits, these relationships deserve further study., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Background: The impact of prenatal lead exposure on neurodevelopment remains unclear in terms of consistency, the trimester of greatest vulnerability, and the best method for estimating fetal lead exposure., Objective: We studied prenatal lead exposure's impact on neurodevelopment using repeated measures of fetal dose as reflected by maternal whole blood and plasma lead levels., Methods: We measured lead in maternal plasma and whole blood during each trimester in 146 pregnant women in Mexico City. We then measured umbilical cord blood lead at delivery and, when offspring were 12 and 24 months of age, measured blood lead and administered the Bayley Scales of Infant Development. We used multivariate regression, adjusting for covariates and 24-month blood lead, to compare the impacts of our pregnancy measures of fetal lead dose., Results: Maternal lead levels were moderately high with a first-trimester blood lead mean (+/- SD) value of 7.1 +/- 5.1 microg/dL and 14% of values >or=10 microg/dL. Both maternal plasma and whole blood lead during the first trimester (but not in the second or third trimester) were significant predictors (p < 0.05) of poorer Mental Development Index (MDI) scores. In models combining all three trimester measures and using standardized coefficients, the effect of first-trimester maternal plasma lead was somewhat greater than the effect of first-trimester maternal whole blood lead and substantially greater than the effects of second- or third-trimester plasma lead, and values averaged over all three trimesters. A 1-SD change in first-trimester plasma lead was associated with a reduction in MDI score of 3.5 points. Postnatal blood lead levels in the offspring were less strongly correlated with MDI scores., Conclusions: Fetal lead exposure has an adverse effect on neurodevelopment, with an effect that may be most pronounced during the first trimester and best captured by measuring lead in either maternal plasma or whole blood.

Purpose: To determine the dose-response relationship between blood lead concentration ([PbB]) and scotopic ERG amplitude in 7- to 10-year-old children with lifetime lead exposure., Methods: Full-field flash scotopic ERGs were recorded over a 4-log-unit range in 45 dark-adapted children with normal visual acuity. [PbB] was measured throughout pregnancy and postnatal development, and the subjects' [PbB] levels were grouped at each age by tertiles., Results: The median [PbB] during pregnancy was, from lowest to highest tertile, 2.5 to 5.0, 7.5 to 9.0, and 14.0 to 16.5 microg/dL, and after birth was 4.0 to 8.0, 6.0 to 14.5, and 7.5 to 21.0 microg/dL. Only maternal [PbB] at 12 weeks of pregnancy showed a significant dose-response relationship with the ERG measures, so that with increasing [PbB] there were significant increases in leading-edge a-wave amplitude, peak a-wave amplitude, and b-wave amplitude and sensitivity, with no changes in implicit times. Data analyses showed that children whose mothers had [PbB] of 10.5 microg/dL or more at 12 weeks of pregnancy had relatively increased a- and b-waves., Conclusions: Lead exposure during the first trimester of pregnancy produces dose-dependent increases in scotopic a- and b-wave amplitudes in 7- to 10-year-old children. The results suggest that the increases in a- and b-wave amplitudes originate from rods; however, the increased b-wave amplitude and sensitivity may also originate in the inner retina. These alterations occurred at maternal [PbB] at or below currently accepted safe levels. These novel findings reveal that the developing retina is a sensitive target for lead and suggest that lead-exposed children be examined for possible future visual system deficits.

BACKGROUND:Although growing evidence suggests that early-life excess manganese (Mn) impairs neurodevelopment, data on the neurodevelopmental effects of mancozeb, a fungicide containing Mn, and its main metabolite ethylenethiourea (ETU) are limited. OBJECTIVE:We examined whether prenatal mancozeb exposure and excess Mn were associated with neurodevelopment in 355 1-y-old infants living near banana plantations with frequent aerial mancozeb spraying in Costa Rica. METHODS:We measured urinary ETU, hair Mn, and blood Mn concentrations in samples collected 1-3 times during pregnancy from mothers enrolled in the Infants' Environmental Health (ISA) study. We then assessed neurodevelopment in their 1-y-old infants using the Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III). We estimated exposure-outcome associations using linear regression models adjusted for maternal education, parity, gestational age at birth, child age, Home Observation for Measurement of the Environment score, and location of neurodevelopmental assessment. RESULTS:Median (P25-P75) urinary ETU, hair Mn, and blood Mn measured during pregnancy were 3.3 μg/L (2.4-4.9; specific gravity-corrected), 1.7 μg/g (0.9-4.1), and 24.0 μg/L (20.3-28.0), respectively. Among girls, higher ETU was associated with lower social-emotional scores [β per 10-fold increase=-7.4 points (95% CI: -15.2, 0.4)], whereas higher hair Mn was associated with lower cognitive scores [-3.0 (-6.1, 0.1)]. Among boys, higher hair Mn was associated with lower social-emotional scores [-4.6 (-8.5, -0.8)]. We observed null associations for blood Mn, language, and motor outcomes. CONCLUSIONS:Our findings indicate that maternal exposure to mancozeb and excess Mn during pregnancy may have adverse and sex-specific effects on infant neurodevelopment. https://doi.org/10.1289/EHP1955.

Background: Temperament is a psychological construct that reflects both personality and an infant's reaction to social stimuli. It can be assessed early in life and is stable over time Temperament predicts many later life behaviors and illnesses, including impulsivity, emotional regulation and obesity. Early life exposure to neurotoxicants often results in developmental deficits in attention, social function, and IQ, but environmental predictors of infant temperament are largely unknown. We propose that prenatal exposure to both chemical and non-chemical environmental toxicants impacts the development of temperament, which can itself be used as a marker of risk for maladaptive neurobehavior in later life. In this study, we assessed associations among prenatal and early life exposure to lead, mercury, poverty, maternal depression and toddler temperament.Methods: A prospective cohort of women living in the Mexico City area were followed longitudinally beginning in the second trimester of pregnancy. Prenatal exposure to lead (blood, bone), mercury, and maternal depression were assessed repeatedly and the Toddler Temperament Scale (TTS) was completed when the child was 24 months old. The association between each measure of prenatal exposure and performance on individual TTS subscales was evaluated by multivariable linear regression. Latent profile analysis was used to classify subjects by TTS performance. Multinomial regression models were used to estimate the prospective association between prenatal exposures and TTS performance.Results: 500 mother-child pairs completed the TTS and had complete data on exposures and covariates. Three latent profiles were identified and categorized as predominantly difficult, intermediate, or easy temperament. Prenatal exposure to maternal depression predicted increasing probability of difficult toddler temperament. Maternal bone lead, a marker of cumulative exposure, also predicted difficult temperament. Prenatal lead exposure modified this association, suggesting that joint exposure in pregnancy to both was most toxic.Conclusions: Maternal depression predicts difficult temperament and concurrent prenatal exposure to maternal depression and lead predicts a more difficult temperament phenotype in 2 year olds. The role of temperament as an intermediate variable in the path from prenatal exposures to neurobehavioral deficits and other health effects deserves further study. [ABSTRACT FROM AUTHOR]

• Lead is a neurotoxicant associated with neurodevelopmental deficits. • Prepulse inhibition (PPI) deficits are associated with neurological disorders. • We estimated the causal effect of prenatal lead exposure on PPI in children. • Our findings suggest prenatal lead exposure causes PPI deficits in children. • PPI may be an objective biomarker of neurotoxicant effects on the brain. During pregnancy, maternal lead from earlier exposures mobilizes and crosses placental barriers, placing the developing fetus at risk for lead exposure and neurodevelopmental deficits. Some neuronal circuits known to be affected in neurodevelopment disorders can be probed with simple physiological behavioral paradigms. One such neural biomarker is Pre-Pulse Inhibition (PPI), an indicator of adequate sensorimotor gating processing. In clinical studies, deficits in PPI have been associated with neurodevelopmental disorders in human subjects. To our knowledge, no studies have examined the use of PPI as a biomarker of toxicant effects on the brain in epidemiological studies. We aimed to estimate the causal effect of prenatal lead exposure, assessed by maternal cortical bone lead concentrations, on PPI in 279 children from Mexico City. in vivo maternal cortical bone lead measurements were taken at four weeks postpartum at the mid-tibia shaft using a K-Shell X-ray fluorescence instrument. PPI recording occurred in an isolated clinical setting and eye blink responses were measured using electromyography. We assessed if the conditions for causal inference held in our study and used the results of our assessment to estimate the causal effect of prenatal lead exposure on PPI using an ordinary least squares regression model, a marginal structural model, and the parametric g-formula. Results were consistent across the three modeling approaches. For the parametric g-formula, a one standard deviation (10.0 μg/g) increase in prenatal lead significantly reduced PPI by approximately 19.0 % (95 % CI: 5.4 %, 34.3 %). This decrease is similar in magnitude to clinical studies on schizophrenia, which have observed PPI impairments in patients with schizophrenia as compared to controls. Our results are consistent with findings from other studies establishing an association between lead exposure and neurodevelopmental disorders in children and suggest that PPI may be useful as an objective biomarker of toxicant effects on the brain. [ABSTRACT FROM AUTHOR]