Objectives: Attention deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurobehavioral disorder of childhood, yet its etiology is not well understood. In this review we present ...evidence that environmental chemicals, particularly polychlorinated biphenyls (PCBs) and lead, are associated with deficits in many neurobehavioral functions that are also impaired in ADHD. Data sources: Human and animal studies of developmental PCB or lead exposures that assessed specific functional domains shown to be impaired in ADHD children were identified via searches of PubMed using "lead" or "PCB exposure" in combination with key words, including "attention," "working memory," "response inhibition," "executive function," "cognitive function," "behavior," and "ADHD." Data synthesis: Children and laboratory animals exposed to lead or PCBs show deficits in many aspects of attention and executive function that have been shown to be impaired in children diagnosed with ADHD, including tests of working memory, response inhibition, vigilance, and alertness. Studies conducted to date suggest that lead may reduce both attention and response inhibition, whereas PCBs may impair response inhibition to a greater degree than attention. Low-level lead exposure has been associated with a clinical diagnosis of ADHD in several recent studies. Similar studies of PCBs have not been conducted. Conclusions: We speculate that exposures to environmental contaminants, including lead and PCBs, may increase the prevalence of ADHD.
Abstract
The placenta guides fetal growth and development. Bisphenol A (BPA) and phthalates are widespread environmental contaminants and endocrine disruptors, and the placental epigenetic response ...to these chemicals is an area of growing research interest. Therefore, our objective was to summarize research linking BPA or phthalate exposure to placental outcomes in human pregnancies, with a particular focus on epigenetic endpoints. In PubMed, studies were selected for review (without limiting start date and ending on 1 May 2018) if they reported any direct effects of BPA or phthalates on the placenta in humans. Collectively, available studies suggest that BPA and phthalate exposures are associated with changes to placental micro-RNA expression, DNA methylation, and genomic imprinting. Furthermore, several studies suggest that fetal sex may be an important modifier of placental outcomes in response to these chemicals. Studies in humans demonstrate associations of BPA and phthalate exposure with adverse placental outcomes. Moving forward, more studies should consider sex differences (termed “placental sex”) in the measured outcomes, and should utilize appropriate statistical approaches to assess modification by fetal sex. Furthermore, more consistent sample collection and molecular outcome assessment paradigms will be indispensable for making progress in the field. These advances, together with improved non-invasive tools for measuring placental function and outcomes across pregnancy, will be critical for understanding the mechanisms driving placental epigenetic disruption in response to BPA and phthalates, and how these disruptions translate into placental and fetal health.
•Cross-pregnancy urinary sum estrogens & testosterones (E&T) mirror blood patterns.•Plasticizer phthalates/replacements associated with increased sum E.•Associations with sum E strongest in later ...gestation in women carrying females.•Personal care phthalates associated with higher sum T and lower E/T ratio.•Associations with sum T and E/T ratio are not gestational age- or sex-specific.
Pregnant women are ubiquitously exposed to phthalates from food packaging materials and personal care products. Phthalates alter estrogen and testosterone concentrations in experimental models, but their ability to impact these hormones in human pregnancy is not well characterized.
We recruited women ages 18–40 into the Illinois Kids Development Study (I-KIDS) in early pregnancy. Participants provided up to 5 first-morning urine samples across pregnancy (8–40 weeks gestation) that we pooled for quantification of 19 phthalate or phthalate alternative metabolites. Either individual (ng/mL) or molar sums (nmol/mL) of metabolites were used as exposure biomarkers. We summed urinary concentrations (ng/mL) of eight major estrogen (SumEstrogens) and two major testosterone (SumTestosterones) metabolites measured at median 13, 28, and 34 weeks gestation. We also estimated the ratio of estrogens-to-androgens. Linear mixed-effects models assessed relationships of phthalates/alternatives as continuous measures or as concentration quartiles with SumEstrogens, SumTestosterones, and the Estrogen/Androgen ratio in 434 women. In our models, we controlled for age, race, education, parity, smoking in the first trimester, pre-pregnancy body mass index, diet quality, conception season, fetal sex, and gestational age at hormone assessment. We also explored whether gestational age at hormone assessment or fetal sex modified these associations. All biomarkers and outcomes were specific gravity-adjusted, and continuous exposures and outcomes were also natural log-transformed.
Most participants were non-Hispanic white (80.9%), college educated (82.2%), and had urinary phthalate/alternative metabolite concentrations similar to those of reproductive-aged U.S. women. Overall, select phthalate metabolites were positively associated with SumEstrogens and SumTestosterones, but negatively associated with the Estrogen/Androgen ratio. For example, SumEstrogens was 5.1% (95%CI: 1.8, 8.5) higher with every 2-fold increase in sum of di(2-ethylhexyl) phthalate metabolites, while SumTestosterones was 7.9% (95%CI: 1.0, 15.3) higher and Estrogen/Androgen ratio was −7.7% (95%CI: −13.6, −1.4) lower with every 2-fold increase in monoethyl phthalate. However, phthalate alternatives were only positively associated with SumEstrogens, which was 2.4% (95%CI: 0.4, 4.5) and 3.2% (95%CI: 0.7, 5.8) higher with every 2-fold increase in sum of di(isononyl) cyclohexane-1,2-dicarboxylate metabolites and sum of di(2-ethylhexyl) terephthalate metabolites, respectively. Gestational age- and fetal sex-specific associations were only consistently observed for associations of phthalates/alternatives with SumEstrogens, where associations were strongest in mid-to-late pregnancy in women carrying females.
Phthalates/alternatives may impact gestational hormones, with potential for gestational age- and fetal sex-specific associations. Whether maternal urinary estrogens and testosterones mediate associations of phthalates/alternatives with pregnancy and fetal outcomes merits further investigation.
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Pregnant women are exposed to multiple phthalates and their replacements, which are endocrine disrupting chemicals associated with adverse maternal and child health outcomes. ...Identifying maternal characteristics associated with phthalate/replacement exposure during pregnancy is important.
We evaluated 13 maternal sociodemographic and lifestyle factors, enrollment year, and conception season as determinants of exposure biomarkers of phthalates and their replacements in 482 pregnant women from the Illinois Kids Development Study (I-KIDS, enrolled 2013–2018). We quantified 19 phthalate/replacement metabolites in pools of five first-morning urines collected across pregnancy. K-means clustering identified women with distinct patterns of biomarker concentrations and principal component analysis (PCA) identified principal component (PC) profiles of biomarkers that exist together. We used multivariable regression models to evaluate associations of predictors with identified k-means clusters and PCs.
K-means clustering identified two clusters of women: 1) low phthalate/di(2-ethylhexyl) terephthalate (∑DEHTP) and 2) high phthalate/∑DEHTP biomarker concentrations. PCA identified four PCs with loadings heaviest for biomarkers of plasticizer phthalates di-isononyl, di-isodecyl, di-n-octyl phthalates (PC1), of other phthalates dibenzyl, di-n-butyl, di-iso-butyl phthalates (PC2), of phthalate replacements ∑DEHTP, di(isononyl) cyclohexane-1,2-dicarboxylate (∑DiNCH) (PC3), and of monoethyl phthalate MEP (PC4). Overall, age, marital status, income, parity, pre-pregnancy BMI, caffeine intake, enrollment year, and conception season were independently associated with k-means cluster membership and at least one PC. Additionally, race/ethnicity, education, employment, pregnancy intention, smoking status, alcohol intake, and diet were associated with at least one PC. For instance, women who conceived in the spring, summer, and/or fall months had lower odds of high phthalate/∑DEHTP cluster membership and had lower plasticizer phthalate, phthalate replacement, and MEP PC scores.
Conception season, enrollment year, and several sociodemographic/lifestyle factors were predictive of phthalate/replacement biomarker profiles. Future studies should corroborate these findings, with a special focus on replacements to which pregnant women are becoming increasingly exposed.
The placenta is critical for all aspects of fetal development. Bisphenol A (BPA) and phthalates are endocrine disruptors with ubiquitous exposure in pregnant women-their effects on the placenta is an ...area of growing research interest. Therefore, our objectives were to (1) summarize research related to the effects BPA or phthalates on placental outcomes in animal and cell models, and (2) evaluate the challenges for using such models to study the impacts of these chemicals on placental endpoints. Overall, studies in cells and animal models suggest that BPA and phthalates impact placental hormones, some epigenetic endpoints, increase inflammation and oxidative stress, and decrease cell viability and nutrient transfer. However, few animal or cell studies have assessed these outcomes at concentrations relevant to humans. Furthermore, it is unclear whether effects of BPA/phthalates on the placenta in animal models mediate fetal outcomes, as most studies have dosed after the earliest stages of placental and fetal development. It is also unclear whether effects of these chemicals are sex-specific, as few studies have considered placental sex. Finally, while there is substantial evidence for effects of mono-(2-ethylhexyl) phthalate (the major metabolite of di-(2-ethylhexyl) phthalate), on placental endpoints in cells, little is currently known about effects of other phthalates to which pregnant women are exposed. Moving forward, these limitations will need to be addressed to help us understand the precise mechanisms of action of these chemicals within the placenta, and how these reported perturbations impact fetal health.
Prenatal exposure to individual per‑ and poly‑fluoroalkyl substances (PFAS) and psychosocial stressors have been associated with reductions in fetal growth. Studies suggest cumulative or joint ...effects of chemical and non-chemical stressors on fetal growth. However, few studies have examined PFAS and non-chemical stressors together as a mixture, which better reflects real life exposure patterns. We examined joint associations between PFAS, perceived stress, and depression, and fetal growth using two approaches developed for exposure mixtures.
Pregnant participants were enrolled in the Chemicals in Our Bodies cohort and Illinois Kids Development Study, which together make up the ECHO.CA.IL cohort. Seven PFAS were previously measured in 2nd trimester maternal serum samples and were natural log transformed for analyses. Perceived stress and depression were assessed using self-reported validated questionnaires, which were converted to t-scores using validated methods. Quantile g-computation and Bayesian kernel machine regression (BKMR) were used to assess joint associations between PFAS, perceived stress and depression t-scores and birthweight z-scores (N = 876).
Individual PFAS, depression and perceived stress t-scores were negatively correlated with birthweight z-scores. Using quantile g-computation, a simultaneous one quartile increase in all PFAS, perceived stress and depression t-scores was associated with a slight reduction in birthweight z-scores (mean change per quartile increase = -0.09, 95% confidence interval = -0.21,0.03). BKMR similarly indicated that cumulative PFAS and stress t-scores were modestly associated with lower birthweight z-scores. Across both methods, the joint association appeared to be distributed across multiple exposures rather than due to a single exposure.
Our study is one of the first to examine the joint effects of chemical and non-chemical stressors on fetal growth using mixture methods. We found that PFAS, perceived stress, and depression in combination were modestly associated were lower birthweight z-scores, which supports prior studies indicating that chemical and non-chemical stressors are jointly associated with adverse health outcomes.
Acetaminophen is currently the only analgesic considered safe for use throughout pregnancy, but recent studies indicate that prenatal exposure to acetaminophen may be related to poorer ...neurodevelopmental outcomes. Multiple studies have suggested that it may be associated with attention problems, but few have examined this association by trimester of exposure. The Illinois Kids Development Study is a prospective birth cohort located in east-central Illinois. Exposure data were collected between December 2013 and March 2020, and 535 newborns were enrolled during that period. Mothers reported the number of times they took acetaminophen at six time points across pregnancy. When children were 2, 3, and 4 years of age, caregivers completed the Child Behavior Checklist for ages 1.5–5 years (CBCL). Associations of acetaminophen use during pregnancy with scores on the Attention Problems and ADHD Problems syndrome scales, the Internalizing and Externalizing Behavior composite scales, and the Total Problems score were evaluated. Higher acetaminophen exposure during the second trimester of fetal development was associated with higher Attention Problems, ADHD Problems, Externalizing Behavior, and Total Problems scores at ages 2 and 3. Higher second trimester exposure was only associated with higher Externalizing Behavior and Total Problems scores at 4 years. Higher cumulative exposure across pregnancy was associated with higher Attention Problems and ADHD Problems scores at ages 2 and 3. Findings suggest that prenatal acetaminophen exposure, especially during the second trimester, may be related to problems with attention in early childhood.
•Prenatal acetaminophen exposure was related to higher attention-related CBCL scores.•More use in especially the second trimester was related to more attention problems.•Increases in CBCL scores were small but apparent at 2, 3, and 4 years of age.•Acetaminophen use in pregnancy may be related to worse attention in early childhood.
Objectives: Attention deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed childhood neurobehavioral disorder. Much research has been done to identify genetic, environmental, and ...social risk factors for ADHD; however, we are still far from fully understanding its etiology. In this review we provide an overview of diagnostic criteria for ADHD and what is known about its biological basis. We also review the neuropsychological functions that are affected in ADHD, The goal is to familiarize the reader with the behavioral deficits that are hallmarks of ADHD and to facilitate comparisons with neurobehavioral deficits associated with environmental chemical exposures. Data sources: Relevant literature on ADHD is reviewed, focusing in particular on meta-analyses conducted between 2004 and the present that evaluated associations between measures of neuropsychological function and ADHD in children. Meta-analyses were obtained through searches of the PubMed electronic database using the terms "ADHD," "meta-analysis," "attention," "executive," and "neuropsychological functions." Although meta-analyses are emphasized, nonquantitative reviews are included for particular neuropsychological functions where no meta-analyses were available. Data synthesis: The meta-analyses indicate that vigilance (sustained attention), response inhibition, and working memory are impaired in children diagnosed with ADHD. Similar but somewhat less consistent meta-analytic findings have been reported for impairments in alertness, cognitive flexibility, and planning. Additionally, the literature suggests deficits in temporal information processing and altered responses to reinforcement in children diagnosed with ADHD. Findings from brain imagining and neurochemistry studies support the behavioral findings. Conclusions: Behavioral, neuroanatomical, and neurochemical data indicate substantial differences in attention and executive functions between children diagnosed with ADHD and non-ADHD controls. Comparisons of the neurobehavioral deficits associated with ADHD and those associated with exposures to environmental chemicals may help to identify possible environmental risk factors for ADHD and/or reveal common underlying biological mechanisms.
The COVID-19 pandemic-and its associated restrictions-have changed many behaviors that can influence environmental exposures including chemicals found in commercial products, packaging and those ...resulting from pollution. The pandemic also constitutes a stressful life event, leading to symptoms of acute traumatic stress. Data indicate that the combination of environmental exposure and psychological stress jointly contribute to adverse child health outcomes. Within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort, a national consortium initiated to understand the effects of environmental exposures on child health and development, our objective was to assess whether there were pandemic-related changes in behavior that may be associated with environmental exposures. A total of 1535 participants from nine cohorts completed a survey via RedCap from December 2020 through May 2021. The questionnaire identified behavioral changes associated with the COVID-19 pandemic in expected directions, providing evidence of construct validity. Behavior changes reported by at least a quarter of the respondents include eating less fast food and using fewer ultra-processed foods, hair products, and cosmetics. At least a quarter of respondents reported eating more home cooked meals and using more antibacterial soaps, liquid soaps, hand sanitizers, antibacterial and bleach cleaners. Most frequent predictors of behavior change included Hispanic ethnicity and older age (35 years and older). Respondents experiencing greater COVID-related stress altered their behaviors more than those not reporting stress. These findings highlight that behavior change associated with the pandemic, and pandemic-related psychological stress often co-occur. Thus, prevention strategies and campaigns that limit environmental exposures, support stress reduction, and facilitate behavioral change may lead to the largest health benefits in the context of a pandemic. Analyzing biomarker data in these participants will be helpful to determine if behavior changes reported associate with measured changes in exposure.
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