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Review of the Existing Evidence for Sex-Specific Relationships between Prenatal Phthalate Exposure and Children's Neurodevelopment.

ABSTRACT: Phthalates are well-known, ubiquitous environmental contaminants influencing children's health and their neurodevelopment. However, results of the previously conducted studies are not entirely conclusive. The aim of this review is to present the current state of knowledge with respect to the association between the prenatal phthalate exposure and sex-specific child neurodevelopmental outcomes. A systematic search of the literature was carried out to identify the studies that analyse the sex-specific association between prenatal exposure to phthalates and cognitive, psychomotor outcomes and behavioural and emotional problems. The search was conducted in May 2021, and it was limited to the papers published in English between January 2015 and April 2021. The following databases were used: PubMed, Scopus and Elsevier. The selection process was carried out by two independent authors according to the inclusion criteria. Of a total of 7542 records, 17 epidemiological studies met the inclusion criteria with regards to phthalate exposure and sex-specific differences in child neurobehavioural development. The review shows no clear pattern of association between maternal exposure to phthalates during pregnancy and offspring neurodevelopment. No clearly pronounced sex specific effects, except for BBzP exposure and decreased motor ablates among girls, have been indicated. Inconsistences in the results, as well as unsolved issues related to the interpretation of the results in the context of the exposure level, outcomes, confounders, and biological plausibility highlight the necessity for further research in the field.

SUBMITTER: Jankowska A

PROVIDER: S-EPMC8700807 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveWe performed a systematic review of the epidemiology literature to identify the neurodevelopmental effects associated with phthalate exposure.Data sources and study eligibility criteriaSix phthalates were included in the review: di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and diethyl phthalate (DEP). The initial literature search (of PubMed, Web of Science, and Toxline) included all studies of neurodevelopmental effects in humans, and outcomes were selected for full systematic review based on data availability.Study evaluation and synthesis methodsStudies of neurodevelopmental effects were evaluated using criteria defined a priori for risk of bias and sensitivity by two reviewers using a domain-based approach. Evidence was synthesized by outcome and phthalate and strength of evidence was summarized using a structured framework. For studies of cognition and motor effects in children ≤4 years old, a random effects meta-analysis was performed.ResultsThe primary outcomes reviewed here are (number of studies in parentheses): cognition (14), motor effects (9), behavior, including attention deficit hyperactivity disorder (20), infant behavior (3), and social behavior, including autism spectrum disorder (7). For each phthalate/outcome combination, there was slight or indeterminate evidence of an association, with the exception of motor effects for BBP, which had moderate evidence.Conclusions and implications of key findingsOverall, there is not a clear pattern of association between prenatal phthalate exposures and neurodevelopment. There are several possible reasons for the observed null associations related to exposure misclassification, periods of heightened susceptibility, sex-specific effects, and the effects of phthalate mixtures. Until these limitations are adequately addressed in the epidemiology literature, these findings should not be interpreted as evidence that there are no neurodevelopmental effects of phthalate exposure. The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.

Project description:BackgroundThe association between exposure to secondhand smoke (SHS) during pregnancy and a child's neurodevelopment has not been established yet. We explored the association between prenatal exposure to SHS and neurodevelopment at 24 months of age considering genetic polymorphism and breastfeeding in 720 mothers and their offspring enrolled in the Korean multicenter birth cohort study (Mothers and Children Environmental Health, MOCEH).MethodsWe quantified urine cotinine concentrations in mothers once from 12th to 20th gestational weeks and excluded those whose urine cotinine levels exceeded 42.7 ng/ml to represent SHS exposure in early pregnancy. Mental developmental index (MDI) and psychomotor developmental index (PDI) values were measured using the Korean version of the Bayley Scales of Infant Development II (K-BSID-II) at 24 months of age. A general linear model was used to assess the relationship between maternal urinary cotinine level and neurodevelopment.ResultsMDI scores were inversely associated with cotinine [β = - 2.73; 95% confidence interval (CI): - 5.32 to - 0.15] in children whose mothers had early pregnancy urinary cotinine levels >1.90 ng/ml. No association was evident in children whose mothers had cotinine levels ≤1.90 ng/ml. This negative association was more pronounced in children whose mothers had both Glutathione S-transferases mu 1 (GSTM1) and theta 1 (GSTT1) null type [β = - 5.78; 95% CI: -10.69 to - 0.87], but not in children whose mothers had any present type of GSTM1/GSTT1 [β = - 1.64; 95% CI: -4.79 to 1.52]. The association was no longer significant when children received breast milk exclusively for up to 6 months [β = - 0.24; 95% CI: -4.69 to 4.20] compared to others [β = - 3.75; 95% CI: -7.51 to 0.00]. No significant association was found for PDI.ConclusionsMaternal exposure to SHS during pregnancy may result in delayed MDI in early childhood. This effect might be modified by genetic polymorphism and breastfeeding behavior.

Project description:Phthalate plasticizers are ubiquitous chemicals linked to several cardiovascular diseases in animal models and humans. Despite this, the mechanisms by which phthalate exposures cause adverse cardiac health outcomes are unclear. In particular, whether phthalate exposures during pregnancy interfere with normal developmental programming of the cardiovascular system, and the resulting implications this may have for long-term disease risk, are unknown. Recent studies suggest that the effects of phthalates on metabolic and neurobehavioral outcomes are sex-specific. However, the influence of sex on cardiac susceptibility to phthalate exposures has not been investigated. One mechanism by which developmental exposures may influence long-term health is through altered programming of DNA methylation. In this work, we utilized an established mouse model of human-relevant perinatal exposure and enhanced reduced representation bisulfite sequencing to investigate the long-term effects of diethylhexyl phthalate (DEHP) exposure on DNA methylation in the hearts of adult male and female offspring at 5 months of age (n = 5-7 mice per sex and exposure). Perinatal DEHP exposure led to hundreds of sex-specific, differentially methylated cytosines (DMCs) and differentially methylated regions (DMRs) in the heart. Pathway analysis of DMCs revealed enrichment for several pathways in females, including insulin signaling, regulation of histone methylation, and tyrosine phosphatase activity. In males, DMCs were enriched for glucose transport, energy generation, and developmental programs. Notably, many sex-specific genes differentially methylated with DEHP exposure in our mouse model were also differentially methylated in published data of heart tissues collected from human heart failure patients. Together, these data highlight the potential role for DNA methylation in DEHP-induced cardiac effects and emphasize the importance of sex as a biological variable in environmental health studies.

Project description:BackgroundFindings from epidemiological studies of prenatal phthalate exposure and child cognitive development are inconsistent. Methods for evaluating mixtures of phthalates, such as weighted quantile sum (WQS) regression, have rarely been applied. We developed a new extension of the WQS method to improve specificity of full-sample analyses and applied it to estimate associations between prenatal phthalate mixtures and cognitive and language outcomes in a diverse pregnancy cohort.MethodsWe measured 22 phthalate metabolites in third trimester urine from mother-child dyads who completed early childhood visits in the Conditions Affecting Neurodevelopment and Learning in Early childhood (CANDLE) study. Language and cognitive ability were assessed using the Bayley Scales of Infant Development (age 3) and the Stanford Binet-5 (age 4-6), respectively. We used multivariable WQS regression to identify phthalate mixtures that were negatively and positively associated with language score and full-scale IQ, in separate models, adjusted for maternal IQ, race, marital status, smoking, BMI, socioeconomic status (SES), child age, sex, and breastfeeding. We evaluated effect modification by sex and SES. If full sample 95% WQS confidence intervals (which are known to be anti-conservative) excluded the null, we calculated a p-value using a permutation test (ppermutation). The performance of this new approach to WQS regression was evaluated in simulated data. We compared the power and type I error rate of WQS regression conducted within datasets split into training and validation samples (WQSSplit) and in the full sample (WQSNosplit) to WQS regression with a permutation test (WQSpermutation). Individual metabolite associations were explored in secondary analyses.ResultsThe analytic sample (N = 1015) was 62.1% Black/31.5% White, and the majority of mothers had a high school education or less (56.7%) at enrollment. Associations between phthalate mixtures and primary outcomes (language score and full-scale IQ) in the full sample were null. Individual metabolites were not associated with IQ, and only one metabolite (mono-benzyl phthalate, MBzP) was associated with Bayley language score (β = -0.68, 95% CI: -1.37, 0.00). In analyses stratified by sex or SES, mixtures were positively and negatively associated with outcomes, but the precision of full-sample WQS regression results were not supported by permutation tests, with one exception. In the lowest SES category, a phthalate mixture dominated by mono-methyl phthalate (MMP) and mono-carboxy-isooctyl phthalate (MCOP) was associated with higher language scores (βlow SES = 2.41, full-sample 95%CI: 0.58, 4.24; ppermutation = 0.04). Performance testing in simulated data showed that WQSpermutation had improved power over WQSSplit (90% versus 56%) and a lower type I error rate than WQSNosplit (7% versus 47%).ConclusionsIn the largest study of these relationships to date, we observed predominantly null associations between mixtures of prenatal phthalates and both language and IQ. Our novel extension of WQS regression improved sensitivity to detect true associations by obviating the need to split the data into training and test sets and should be considered for future analyses of exposure mixtures.

Project description:Compared with the relatively well-investigated effects of childhood exposure to lead on neurocognitive deficits, those of prenatal exposure remain relatively inconclusive. We aimed to investigate the association between prenatal blood lead levels and neurodevelopmental delay during the first three years of life. From a prospective cohort of the Japan Environment and Children's Study, we analyzed a total of 80,759 children. The exposure factors were prenatal lead concentrations measured from maternal whole blood in the second/third trimesters and umbilical cord blood at birth. Neurodevelopment was assessed at 6, 12, 18, 24, 30, and 36 months old using a screening tool, the Ages and Stages Questionnaires, third edition (ASQ). The outcome measures were any suspected neurodevelopmental delay (sNDD) identified via the ASQ during the first (sNDD-1Y), second (sNDD-2Y), and third (sNDD-3Y) years of life. sNDD-1Y, 2Y, and 3Y were identified in 18.0%, 16.2%, and 17.2% of children, respectively. The geometric means of blood lead concentration in this study were much lower (0.62 μg/dL in maternal blood and 0.50 μg/dL in cord blood) than previously investigated levels. Multivariable regression models revealed that there were no associations between maternal blood lead and sNDD-1Y and 2Y and between cord blood lead and sNDD-1Y, 2Y, and 3Y. Although a higher maternal blood lead was associated with a reduced risk of sNDD-3Y (adjusted relative risk: 0.84, 95% confidence interval 0.75-0.94, per 1 increase in common logarithm of lead concentration), there were no dose-response relationships in the analysis using quintiles of lead concentrations. Using a large-scale data set, the present study demonstrated no convincing evidence for an inverse association between levels of prenatal blood lead and neurodevelopment in early childhood. Longitudinal measurements of prenatal and postnatal lead levels are needed to understand the relationship between lead exposure and neurocognitive development.

Project description:Phthalates, a class of chemicals found widely in consumer products including plastic toys, food contaminants and food packaging, personal care products, cosmetics, air fresheners, and some medications, have been shown to be anti-androgenic in numerous laboratory and epidemiological studies. In a prior cohort enrolled in 2000-2002, we observed associations between prenatal urinary concentrations of di-ethyl hexyl phthalate (DEHP) and dibutyl phthalate (DBP) metabolites and less male-typed play behavior in preschool age boys. The aim of this study was to examine phthalate exposure in pregnancy in relation to play behavior at age 4 years in a larger cohort of pregnant women enrolled in The Infant Development and the Environment Study (TIDES) between 2010 and 2012 at four study sites (Minneapolis, MN; Rochester, NY; San Francisco, CA; Seattle, WA). Maternal urinary metabolites of DEHP, DiBP, DnBP, BBzP, and DEP were measured during the first (n=498) and third trimester (n=468) and mothers completed the Preschool Activities Inventory (PSAI), a validated maternal questionnaire designed to assess child toy preference and sex-typed play behavior when children were 4-5 years of age. After adjusting for child age, maternal education, race, urine dilution, parental attitudes about opposite sex-typed play behavior, and presence of a same sex older sibling, we observed associations between first trimester (mean 10.7±2.1 weeks gestation) (log10) SpG-adjusted MnBP, MiBP, and MBzP and lower masculine scores in boys (β-coefficient [95% confidence intervals]: MnBP -2.18, [-4.16, -0.20]), MiBP -2.1[-4.3,0.1], and MBzP -2.42 [-4.12, -0.71]). In girls, first trimester maternal urinary MBzP was associated with lower masculine scores (-2.12 [-3.98,-0.25]), while third trimester (mean 32.8±3.0 weeks gestation) maternal urinary MiBP was associated with higher masculine scores (2.69 [0.68,4.70]). Third trimester maternal urinary phthalate levels were not associated with play behavior in boys. These findings in boys are largely consistent with previous studies that report that prenatal phthalate exposure is associated with less masculine play behavior. No associations in girls have been previously reported.

Project description:Exposure to phthalates has been shown to impede the human endocrine system, resulting in deleterious effects on pregnant women and their children. Phthalates modify DNA methylation patterns in infant cord blood. We examined the association between prenatal phthalate exposure and DNA methylation patterns in cord blood in a Korean birth cohort. Phthalate levels were measured in 274 maternal urine samples obtained during late pregnancy and 102 neonatal urine samples obtained at birth, and DNA methylation levels were measured in cord blood samples. For each infant in the cohort, associations between CpG methylation and both maternal and neonate phthalate levels were analyzed using linear mixed models. The results were combined with those from a meta-analysis of the levels of phthalates in maternal and neonatal urine samples, which were also analyzed for MEOHP, MEHHP, MnBP, and DEHP. This meta-analysis revealed significant associations between the methylation levels of CpG sites near the CHN2 and CUL3 genes, which were also associated with MEOHP and MnBP in neonatal urine. When the data were stratified by the sex of the infant, MnBP concentration was found to be associated with one CpG site near the OR2A2 and MEGF11 genes in female infants. In contrast, the concentrations of the three maternal phthalates showed no significant association with CpG site methylation. Furthermore, the data identified distinct differentially methylated regions in maternal and neonatal urine samples following exposure to phthalates. The CpGs with methylation levels that were positively associated with phthalate levels (particularly MEOHP and MnBP) were found to be enriched genes and related pathways. These results indicate that prenatal phthalate exposure is significantly associated with DNA methylation at multiple CpG sites. These alterations in DNA methylation may serve as biomarkers of maternal exposure to phthalates in infants and are potential candidates for investigating the mechanisms by which phthalates impact maternal and neonatal health.

Project description:BACKGROUND:Previous studies suggest that prenatal exposure to phthalates, ubiquitous synthetic chemicals, may adversely affect neurodevelopment. However, data are limited on how phthalates affect cognition, executive function, and behavioral function into adolescence. OBJECTIVE:We aimed to investigate associations of prenatal phthalate exposure with neurodevelopment in childhood and adolescence in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. METHODS:We examined associations between maternal urinary phthalate metabolite concentrations measured twice during pregnancy and a range of neurodevelopmental outcomes from ages 7 through 16 y in the CHAMACOS birth cohort (n=334). We used age-specific linear regression models and generalized estimating equation models to assess longitudinal effects and examined differences by sex. RESULTS:Phthalate metabolites were detected in 88%-100% of samples, depending on the metabolite. Associations of phthalates with neurodevelopmental outcomes were largely null with some noteworthy patterns. Higher prenatal concentrations of metabolites of low-molecular weight phthalates (?LMW) were associated with more self-reported hyperactivity [?=0.8, 95% confidence interval (CI): 0.1, 1.4 per 2-fold increase in ?LMW phthalates], attention problems (?=1.5, 95% CI: 0.7, 2.2), and anxiety (?=0.9, 95% CI: 0.0, 1.8) at age 16. We observed sex-specific differences for the sums of high-molecular-weight and di(2-ethylhexyl) metabolites and cognitive outcomes (e.g., ? for Full-Scale IQ for boys=-1.9, 95% CI: -4.1, 0.3 and -1.7, 95% CI: -3.8, 0.3, respectively; ? for girls=1.8, 95% CI: 0.1, 3.4 and 1.6, 95% CI: 0.0, 3.2, respectively; p-int=0.01 for both). CONCLUSION:We found predominantly null associations of prenatal phthalates with neurodevelopment in CHAMACOS, and weak associations of ?LMW phthalates with internalizing and externalizing behaviors in adolescence. No previous studies have examined associations of prenatal phthalate exposure with neurodevelopment into adolescence, an important time for manifestations of effects. https://doi.org/10.1289/EHP5165.

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Review of the Existing Evidence for Sex-Specific Relationships between Prenatal Phthalate Exposure and Children's Neurodevelopment.

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