Maternal Urinary Phthalate Metabolites Research Articles

Paternal and maternal preconception and maternal pregnancy urinary phthalate metabolite and BPA concentrations in relation to child behavior

BackgroundEpidemiologic studies on health effects of parental preconception exposures are limited despite emerging evidence from toxicological studies suggesting that such exposures, including to environmental chemicals, may affect offspring health. ObjectiveWe investigated whether maternal and paternal preconception and maternal pregnancy urinary phthalate metabolite and bisphenol A (BPA) concentrations were associated with child behavior. MethodsWe analyzed data from the Preconception Environmental exposure And Childhood health Effects (PEACE) Study, an ongoing prospective cohort study of children aged 6–11 years whose parent(s) previously enrolled in the prospective preconception Environment and Reproductive Health (EARTH) study. Using linear mixed models, we estimated covariate-adjusted associations of 11 urinary phthalate metabolite and BPA concentrations collected prior to conception and during pregnancy with Behavioral Assessment System for Children-3 (BASC-3) T-scores (higher scores indicate more problem behaviors). ResultsThis analysis included 134 mothers, 87 fathers and 157 children (24 sets of twins); parents were predominantly non-Hispanic white (mothers and fathers86%). Higher maternal preconception or pregnancy monobenzyl phthalate (MBzP) concentrations were related to higher mean externalizing problems T-scores in their children (β = 1.3 per 1-loge unit increase; 95 % CI: −0.2, 2.4 and β = 2.1, 95 % CI: 0.7, 3.6, respectively). Higher maternal preconception monocarboxyoctyl phthalate (MCOP) was suggested to be related to lower mean externalizing problems T-scores (β = -0.9; 95 % CI: −1.8, 0.0). Higher paternal preconception MCOP was suggestively associated with lower internalizing problems (β = -0.9; 95 %CI:-1.9, 0.1) and lower Behavioral Symptoms Index (BSI) T-scores (β = -1.3; 95 % CI: −2.1, −0.4). ConclusionIn this cohort, higher maternal preconception and pregnancy MBzP were associated with worse parent-reported child behavior, while higher maternal and paternal preconception MCOP concentrations were related to lower BASC-3 scores.

Maternal urinary phthalate metabolites during pregnancy and thyroid function: The MAKE Study

Maternal urinary phthalate metabolites during pregnancy and thyroid function: The MAKE Study

A study on the association of placental and maternal urinary phthalate metabolites.

Phthalate exposure in pregnancy is typically estimated using maternal urinary phthalate metabolite levels. Our aim was to evaluate the association of urinary and placental tissue phthalates, and to explore the role of maternal and pregnancy characteristics that may bias estimates. Fifty pregnancies were selected from the CANDLE Study, recruited from 2006 to 2011 in Tennessee. Linear models were used to estimate associations of urinary phthalates (2nd, 3rd trimesters) and placental tissue phthalates (birth). Potential confounders and modifiers were evaluated in categories: temporality (time between urine and placenta sample), fetal sex, demographics, social advantage, reproductive history, medication use, nutrition and adiposity. Molar and quantile normalized phthalates were calculated to facilitate comparison of placental and urinary levels. Metabolites detectable in >80% of both urine and placental samples were MEP, MnBP, MBzP, MECPP, MEOHP, MEHHP, and MEHP. MEP was most abundant in urine (geometric mean [GM] 7.00 ×102 nmol/l) and in placental tissue (GM 2.56 ×104 nmol/l). MEHP was the least abundant in urine (GM 5.32 ×101 nmol/l) and second most abundant in placental tissue (2.04 ×104 nmol/l). In aggregate, MEHP differed the most between urine and placenta (2.21 log units), and MEHHP differed the least (0.07 log units). MECPP was positively associated between urine and placenta (regression coefficient: 0.31 95% CI 0.09, 0.53). Other urine-placenta metabolite associations were modified by measures of social advantage, reproductive history, medication use, and adiposity. Phthalates were ubiquitous in 50 full-term placental samples, as has already been shown in maternal urine. MEP and MEHP were the most abundant. Measurement and comparison of urinary and placental phthalates can advance knowledge on phthalate toxicity in pregnancy and provide insight into the validity and accuracy of relying on maternal urinary concentrations to estimate placental exposures. This is the first report of correlations/associations of urinary and placental tissue phthalates in human pregnancy. Epidemiologists have relied exclusively on maternal urinary phthalate metabolite concentrations to assess exposures in pregnant women and risk to their fetuses. Even though it has not yet been confirmed empirically, it is widely assumed that urinary concentrations are strongly and positively correlated with placental and fetal levels. Our data suggest that may not be the case, and these associations may vary by phthalate metabolite and associations may be modified by measures of social advantage, reproductive history, medication use, and adiposity.

Maternal urinary phthalate metabolites are associated with lipidomic signatures among pregnant women in Puerto Rico.

Background:Phthalates have been reported to alter circulating lipid concentrations in animals, and investigation of these associations in humans will provide greater understanding of potential mechanisms for health outcomes.Objective:to explore associations between phthalate metabolite biomarkers and lipidomic profiles among pregnant women (n = 99) in the Puerto Rico PROTECT cohort.Methods:We measured 19 urinary phthalate metabolites during 24–28 weeks of pregnancy. Lipidomic profiles were identified from plasma samples by liquid chromatography-mass spectrometry-based shotgun lipidomics. Relationships between phthalate metabolites and lipid profiles were estimated using compound-by-compound comparisons in multiple linear regression and dimension reduction techniques. We derived sums for each lipid class and sub-class (saturated, monounsaturated, polyunsaturated) which were then regressed on phthalate metabolites. Associations were adjusted for false discovery.Results:After controlling for multiple comparisons, 33 phthalate-lipid associations were identified (False discovery rate adjusted p-value<0.05), and diacylglycerol 40:7 and plasmenyl-phosphatidylcholine 35:1 were the most strongly associated with multiple phthalate metabolites. Metabolites of di-2-ethylhexyl phthalate, bis(2-ethylhexyl) phthalate, dibutyl phthalates, and diisobutyl phthalate were associated with increased ceramides, lysophosphatidylcholines, lysophosphatidylethanolamines, and triacylglycerols, particularly those containing saturated and monounsaturated fatty acid chains.Significance:Characterization of associations between lipidomic markers and phthalate metabolites during pregnancy will yield mechanistic insight for maternal and child health outcomes.

First- and Third-Trimester Urinary Phthalate Metabolites in the Development of Hypertensive Diseases of Pregnancy.

The purpose of this study was to determine whether maternal urinary phthalate metabolite concentrations are associated with the development of higher blood pressure or pregnancy-induced hypertension (PIH). Participants were women without chronic hypertension who enrolled in The Infant Development and the Environment Study, a prospective pregnancy cohort conducted at four U.S. academic medical centers from 2010–2012. Prenatal records were reviewed to obtain blood pressure measurements and diagnoses of PIH (gestational hypertension, preeclampsia, eclampsia, and HELLP syndrome, defined as hemolysis, elevated liver enzymes, and low platelet count). Complete-case analyses used multivariable linear and logistic regression for analysis of blood pressure measurements and PIH diagnoses, respectively. In the final dataset (N = 668), higher concentrations of first-trimester monoethyl phthalate (MEP) and mono-3-carboxypropyl phthalate (MCPP) and third-trimester mono-isobutyl phthalate (MiBP) were significantly associated with a medical chart diagnosis of PIH. First-trimester mono-n-butyl phthalate (MBP) and MEP along with the sum of di-(2-ethylhexyl) phthalate metabolites (∑DEHP) were each associated with increased systolic blood pressure across pregnancy. In conclusion, several phthalate metabolite concentrations were significantly associated with PIH and greater increases in systolic blood pressure across pregnancy.

The association between maternal urinary phthalate metabolites concentrations and pregnancy induced hypertension: Results from the EDEN Mother-Child Cohort

BackgroundStudies have suggested that exposure to endocrine disruptors such as phthalates that are widely used in our daily life (food wrapping, cosmetics, toys, medical devices, polyvinyl chloride flooring, and building materials) might be related to raised blood pressure and increased risk of cardiovascular diseases. Phthalates might induce a pro-inflammatory response and increased oxidative stress and may be a cause of pregnancy induced hypertension. MethodsWe evaluated the association between maternal exposure to phthalates during pregnancy and pregnancy induced hypertension. 604 pregnant women were included and eleven phthalate metabolites were quantified in spot maternal urine samples collected between the 23rd and 28th week of gestation in a French EDEN mother-child cohort. The associations were assessed by applying multiple logistic regression analysis. ResultsTwenty nine (4,8%) mothers developed pregnancy induced hypertension. Two low molecular weight phthalate metabolites: Monoethyl phthalate (MEP) and Mono-n‑butyl phthalate (MBP) were positively associated with pregnancy induced hypertension in crude (Odds Ratio: 1.43, 95% Confidence Interval: 1.04–1.96, p-value = 0.02 and 1.48, 1.10–2.01, p-value =0.01) and in adjusted (1.47, 1.01–2.14, p-value = 0.04 and 1.66, 1.11–2.47, p-value = 0.01) models respectively. ConclusionOur data suggest that prenatal exposure to some phthalates, including MEP and MBP, might play a role in pregnancy induced hypertension.

A Comprehensive Assessment of Associations between Prenatal Phthalate Exposure and the Placental Transcriptomic Landscape.

Background:Phthalates are commonly used endocrine-disrupting chemicals that are ubiquitous in the general population. Prenatal phthalate exposure may alter placental physiology and fetal development, leading to adverse perinatal and childhood health outcomes.Objective:We examined associations between prenatal phthalate exposure in the second and third trimesters and the placental transcriptome at birth, including genes and long noncoding RNAs (lncRNAs), to gain insight into potential mechanisms of action during fetal development.Methods:The ECHO PATHWAYs consortium quantified 21 urinary phthalate metabolites from 760 women enrolled in the CANDLE study (Shelby County, TN) using high-performance liquid chromatography–tandem mass spectrometry. Placental transcriptomic data were obtained using paired-end RNA sequencing. Linear models were fitted to estimate separate associations between maternal urinary phthalate metabolite concentration during the second and third trimester and placental gene expression at birth, adjusted for confounding variables. Genes were considered differentially expressed at a Benjamini-Hochberg false discovery rate (FDR) . Associations between phthalate metabolites and biological pathways were identified using self-contained gene set testing and considered significantly altered with an FDR-adjusted .Results:We observed significant associations between second-trimester phthalate metabolites mono (carboxyisooctyl) phthalate (MCIOP), mono-2-ethyl-5-carboxypentyl phthalate, and mono-2-ethyl-5-oxohexyl phthalate and 18 genes in total, including four lncRNAs. Specifically, placental expression of NEAT1 was associated with multiple phthalate metabolites. Third-trimester MCIOP and mono-isobutyl phthalate concentrations were significantly associated with placental expression of 18 genes and two genes, respectively. Expression of genes within 27 biological pathways was associated with mono-methyl phthalate, MCIOP, and monoethyl phthalate concentrations.Discussion:To our knowledge, this is the first genome-wide assessment of the relationship between the placental transcriptome at birth and prenatal phthalate exposure in a large and diverse birth cohort. We identified numerous genes and lncRNAs associated with prenatal phthalate exposure. These associations mirror findings from other epidemiological and in vitro analyses and may provide insight into biological pathways affected in utero by phthalate exposure. https://doi.org/10.1289/EHP8973

Maternal Food and Beverage Consumption Behaviors and Discrepant Phthalate Exposure by Race.

Background: Differential exposure to endocrine-disrupting chemicals, including phthalate diesters, may contribute to persistent racial/ethnic disparities in women’s reproductive health outcomes. We sought to characterize sources of gestational exposure to these agents that may differ according to maternal race. Methods: We enrolled pregnant Black (n = 198), including African American, and White (n = 197) women during the second trimester, and measured eight phthalate monoester metabolites in urine. We assessed confounder-adjusted associations between multiple food and beverage consumption habits, summarized using a principal component analysis, as predictors of maternal urinary phthalate metabolite levels, stratified by race. Results: Whites reported significantly greater unprocessed food consumption (42.5% vs. 32.0%; p < 0.001) and storage of food in clear unbreakable plastic containers (66.5% vs. 49.3%; p < 0.001) than Blacks, while Blacks consumed more canned fruits and vegetables (23.5% vs. 12.2%; p < 0.001) than Whites. Using plastics for food storage, microwaving in plastic containers, and using hard plastic water bottles was associated with urinary phthalate concentrations, especially DEHP metabolites (e.g., mean difference = 5.13%; 95% CI: 3.05, 7.25). These associations were driven primarily by Black pregnant women. Conclusions: Targeted interventions to reduce maternal exposure to phthalates need to be designed with specific attention to differences in food and beverage consumption behaviors among Black and White women.

Phthalate mixtures in pregnancy, autistic traits, and adverse childhood behavioral outcomes

BackgroundPrenatal exposure to multiple phthalates is ubiquitous, and yet few studies have evaluated these exposures as a mixture in relation to child autistic traits and behavioral problems. ObjectivesTo assess cumulative associations between prenatal phthalate mixtures and child behaviors, including effect modification by exposure timing and child sex. MethodsAnalyses included 501 mother/child pairs from the multicenter pregnancy cohort The Infant Development and Environment Study (TIDES). Nine maternal urinary phthalate metabolites were measured in early and late pregnancy, and behavior was assessed at ages 4–5 years using composite T scores for the Behavioral Assessment System for Children (BASC-2), which measures several dimensions of child behavior, and the Social Responsiveness Scale (SRS-2), which measures social impairment consistent with autistic traits. We utilized weighted quantile sum (WQS) regressions to examine pregnancy period-specific associations between phthalate mixtures and behavioral outcomes. Full-sample 95% WQS confidence intervals are known to be anti-conservative, so we calculated a confirmatory p-value using a permutation test. Effect modification by sex was examined with stratified analyses. ResultsA one-quintile increase in the early pregnancy phthalate mixture was associated with increased SRS-2 total score (coefficient = 1.0, confirmatory p = 0.01) and worse adaptive skills (coefficient = −1.0, confirmatory p = 0.06) in both sexes. In sex-stratified analyses, the early pregnancy phthalate mixture was associated with increased SRS-2 total score in boys (coefficient = 1.2, confirmatory p = 0.04) and girls (coefficient = 1.0, confirmatory p = 0.10) and worse BASC-2 adaptive skills score in girls (coefficient = −1.5, confirmatory p = 0.06), while the late pregnancy phthalate mixture was associated with increased BASC-2 externalizing score in boys (coefficient = 1.3, confirmatory p = 0.03). ConclusionOur results suggest cumulative adverse associations between prenatal phthalate mixtures and multiple facets of childhood behavior.

Prenatal phthalate exposures and autism spectrum disorder symptoms in low-risk children

BackgroundPrenatal exposure to environmental chemicals has been associated with Autism Spectrum Disorder (ASD) symptoms in some, but not all, studies, but most research has not accounted for other childhood behavior problems. ObjectivesTo evaluate the specific associations of prenatal phthalate exposures with ASD symptoms in children (ages 3–6) accounting for other behavior problems, and to assess sex differences in these associations. MethodsWe measured phthalate metabolites in prenatal urine samples. Mothers completed the Social Responsiveness Scale-2nd edition (SRS-2) to assess child ASD symptoms and the Child Behavior Checklist (CBCL) to assess general behavior problems. We assessed associations of the sum of di-(2-ethylhexyl) phthalate metabolites, monobutyl phthalate, mono-isobutyl phthalate, and monoethyl phthalate (mEP) with ASD symptoms, adjusting for other behavior problems, using linear regression models (n=77). ResultsMost associations were null, and the sample size limited power to detect associations, particularly in the stratified analyses. After adjusting for internalizing and externalizing problems from the CBCL, ASD symptoms increased for each doubling of prenatal mEP concentration among boys only. ConclusionsFurther investigation of maternal prenatal urinary phthalate metabolite concentrations and ASD symptoms while adjusting for other behavioral problems is warranted.

Maternal Urinary Phthalate Metabolites are Associated with Lipidomic Profiles Among Pregnant Women in Puerto Rico

Background/Aim: Endocrine disrupting chemicals (EDCs) such as phthalates have been reported to alter circulating lipid concentrations in animals, however, the relationship has rarely been investigated among humans. We assessed associations between phthalate metabolite biomarkers and lipidomic profiles among pregnant women (n = 99) in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort.Methods: We measured 19 urinary phthalate or phthalate replacement chemical metabolites during 24-28 weeks of pregnancy. Prenatal plasma lipidomic profiles were identified by liquid chromatography-mass spectrometry-based shotgun lipidomics. Multiple statistical strategies were used to assess relationships between phthalates and lipid profiles, including compound-by-compound comparisons using multiple linear regression and various dimension reduction techniques. We derived sums for each lipid class, sums for each lipid sub-class (saturated, monounsaturated, polyunsaturated), and used principal component analysis (PCA) to derive the principal component of each lipid class, which were then regressed on phthalates. Hierarchical clustering and multivariate analyses were also used for further investigation. False discovery rate (FDR) adjusted p-values (q-values) were used to account for multiple comparisons.Results: A total of 587 unique lipids from 19 lipid classes were profiled. When controlling for multiple comparisons, 47 phthalate-lipid associations remained highly significant (p-value&lt;0.001, q-value&lt;0.1). Lipid patterns constructed from PCA accounted for 30~57% of the variation for each lipid class. Mono(2-ethyl-5-carboxypentyl) phthalate (MECCP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and the sum of dibutyl phthalates (ΣDBP) were associated with increased lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and phosphatidic acid (PA) lipid groups, particularly those containing saturated and monounsaturated fatty acid chains. This is consistent with the top associations selected from the compound-by-compound analysis. Cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH) was also associated with higher polyunsaturated triglyceride (TG).Conclusion: Certain phthalate/phthalate replacement biomarkers were associated with lipids integral to cell structure and function. Linking these lipid patterns with health parameters will be an important future step.

Prenatal phthalate exposures and anthropometryduring adolescence: The HOME Study

Background/Aim: Phthalate exposures are ubiquitous in pregnant women and may be obesogenic. Although excess adolescent adiposity predicts obesity and cardiometabolic diseases during adulthood, few studies have examined associations between prenatal phthalate exposures and anthropometric outcomes during adolescence. We investigated the relationships between prenatal phthalate exposures and anthropometry at age 12 years.Methods: We used data from 219 mother-child pairs enrolled in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort enrolled in Cincinnati, OH from 2003-2006. We measured monobutyl phthalate (MnBP), monobenzyl phthalate (MBzP), mono-(3-carboxypropyl) phthalate (MCPP), monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), and four metabolites of di-2-ethylhexyl phthalate (DEHP) in maternal urine samples collected at 16 and 26 weeks of pregnancy. At age 12 years, we measured child weight and height. We used multivariable linear regression to estimate covariate-adjusted associations of a 10-fold increase in average maternal urinary phthalate metabolite concentrations with age- and sex- standardized height, weight, and BMI z-scores. We assessed effect measure modification (EMM) by child sex using stratified models.Results: In adjusted analyses, maternal urinary phthalate metabolite concentrations were not associated with height, weight, or BMI z-scores in the overall sample. However, associations of MBzP concentrations with all anthropometry z-scores were modified by child sex, with lower z-scores among girls, but not boys. For example, a 10-fold increase in MBzP concentrations was associated with lower BMI z-scores in girls (β=-0.4; 95% CI: -0.9, 0.0) but not boys (β=0.2; 95% CI: -0.3, 0.7; EMM p-value=0.09). Additionally, a 10-fold increase in MiBP was associated with increased height z-scores among boys (β=0.7; 95% CI: 0.1, 1.3), but not girls (β=0.0; 95% CI: -0.6, 0.5; EMM p-value=0.09).Conclusions: In this prospective cohort study, higher prenatal phthalate exposures were not associated with adolescent anthropometry, but there may be sex-specific effects.

Fetal exposure to phthalates and bisphenols and childhood general and organ fat. A population-based prospective cohort study.

Fetal exposure to phthalates and bisphenols might have long-lasting effects on growth and fat development. Not much is known about the effects on general and organ fat development in childhood. We assessed the associations of fetal exposure to phthalates and bisphenols with general and organ fat measures in school-aged children. In a population-based, prospective cohort study among 1128 mother-child pairs, we measured maternal urinary phthalate metabolites and bisphenol concentrations in first, second, and third trimester. Offspring body mass index, fat mass index by dual-energy X-ray absorptiometry, and visceral and pericardial fat indices and liver fat fraction were measured by magnetic resonance imaging at 10 years. After adjustment for confounders and correction for multiple testing, an interquartile range increase in first trimester phthalic acid concentrations remained associated with a 0.14 (95% confidence interval: 0.05, 0.22) standard deviation score increase in pericardial fat index. We also observed tendencies for associations of higher maternal low molecular weight phthalate urinary concentrations in second trimester with childhood pericardial fat index, but these were not significant after adjustment for multiple testing. High molecular weight phthalate, di-2-ethylhexyl phthalate, and di-n-octyl phthalate concentrations were not associated with childhood outcomes. Maternal urinary bisphenol concentrations were not associated with childhood adiposity. Maternal first trimester phthalic acid concentrations are associated with increased childhood pericardial fat index at 10 years of age, whereas maternal bisphenol concentrations are not associated with childhood adiposity. We did not find significant sex-specific effects. These findings should be considered as hypothesis generating and need further replication and identification of underlying mechanisms.

Prenatal exposure to phthalate esters and its associations with childhood allergies (TMICS Study)

TPS 752: Respiratory effects and allergies, Exhibition Hall, Ground floor, August 27, 2019, 3:00 PM - 4:30 PM Background/Aim: The relationships between prenatal exposure to specific phthalate and childhood allergies were inconsistent in previous epidemiologic studies. Various exposure levels may explain it. The Taiwanese reduced phthalates exposure after the food scandal in 2011. We aimed to examine the associations between prenatal exposure to selected phthalates and childhood allergies. Methods: The Taiwan Maternal and Infant Cohort Study (TMICS) enrolled pregnant women at third trimester in 2012-2015. Data for maternal urinary phthalate metabolites and health conditions in 3-year-old child were collected from 213 singleton-and-mother pairs. Eight phthalate metabolites in maternal urine were measured by liquid chromatography/electrospray tandem mass spectrometry (LC–ESI-MS/MS). Level of di-2-ethylhexyl phthalate (DEHP) was sum of nanomolar concentration of mono-(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP). Titers of total immunoglobulin E (total IgE) in children were measured by paper radio immuno-sorbent test (PRIST). Sociodemographic characteristics, delivery records, and living environment information were collected via questionnaire. Allergic symptoms and diagnoses were self-reported by mothers in the questionnaire developed by International Study of Asthma and Allergies in Childhood (ISAAC). Binary logistic regression model and linear regression model were used to examine relationships between childhood allergies and dichotomized phthalate metabolites (> 2nd tertile vs. <=2nd tertile). Results: After adjustment for potential confounders, increased risk of symptomatic rhinoconjunctivitis in children was associated with higher prenatal exposure to monoethyl phthalate (adjusted odds ratio [95% confidence interval]): 0.34[0.12-0.93], symptoms and diagnoses of eczema were both positively associated with MEHP (3.32 [1.05-10.53] and 3.93 [1.20-12.89], respectively) and MEOHP (3.93 [1.26-12.24] and 4.14 [1.34-12.79], respectively). None of eight phthalates was associated with total IgE concentration in children. Conclusions: According to exposure level in TMICS, prenatal exposure to MEHP and MEOHP were still related to increased risk of eczema; however, prenatal exposure to MEP may be associated with decreased risk of rhinoconjunctivitis in toddlers.

Prenatal Exposure to Phthalates and Neurodevelopment in the CHAMACOS Cohort

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 (). 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 () were associated with more self-reported hyperactivity [, 95% confidence interval (CI): 0.1, 1.4 per 2-fold increase in phthalates], attention problems (, 95% CI: 0.7, 2.2), and anxiety (, 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 , 95% CI: , 0.3 and , 95% CI: , 0.3, respectively; for , 95% CI: 0.1, 3.4 and 1.6, 95% CI: 0.0, 3.2, respectively; for both).Conclusion:We found predominantly null associations of prenatal phthalates with neurodevelopment in CHAMACOS, and weak associations of 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

Associations of Phthalates and Phthalate Replacements With CRH and Other Hormones Among Pregnant Women in Puerto Rico.

ContextPhthalates are endocrine-disrupting chemicals that may be associated with adverse birth outcomes. Dysregulation of maternal endocrine homeostasis could be a possible biological pathway between phthalates and birth outcomes.ObjectiveExamine associations between 19 maternal urinary phthalate or phthalate replacement metabolites and 9 serum hormones measured over two time points during pregnancy.DesignLongitudinal study conducted in the PROTECT pregnancy cohort.SettingPuerto Rico.PatientsSix hundred seventy-seven women in the first trimester of pregnancy.Main Outcome Measures SerumCRH, estriol, SHBG, progesterone, TSH, total T3, free T4, total T4, and testosterone.ResultsT3 was significantly associated with most metabolites. CRH was inversely associated with mono carboxyisononyl phthalate [MCNP; percent change (%Δ), −4.08; 95% CI, −7.24, −0.804], mono-3-carboxypropyl phthalate (MCPP; %Δ, −5.25; 95% CI, −8.26, −2.14), mono-2-ethyl-5-carboxypentyl phthalate (MECPP; %Δ, −18.4; 95% CI, −30.4, −4.37), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP; %Δ, −13.4; 95% CI, −22.7, −2.92), and mono-2-ethyl-5-oxohexyl phthalate (MEOHP; %Δ, −12.7; 95% CI, −22.2, −2.20). Positive associations were found between numerous phthalate metabolites and free T4, T4, and the T3/T4 ratio. Testosterone was positively associated with mono hydroxybutyl phthalate (MHBP; %Δ, 4.71; 95% CI, 0.27, 9.35) and inversely associated with monoethyl phthalate (MEP; %Δ, −14.5; 95% CI, −24.3, −3.42), and relationships with MCNP and mono carboxyisooctyl phthalate (MCOP) were significantly modified by study visit. Finally, an inverse association was found between mono-2-ethyl-5-hydrohexyl terephthalate (MEHHTP), a terephthalate metabolite, and progesterone at visit 3 only (%Δ, −13.1; 95% CI, −22.3, −2.75).ConclusionsThese results indicate that exposure to phthalates may differentially impact the maternal endocrine system at different points during pregnancy, and that exposures to phthalate replacement chemicals may be particularly important to consider in future human health studies.

Racial disparity in maternal phthalates exposure; Association with racial disparity in fetal growth and birth outcomes

Experimental and observational data implicate phthalates as developmental toxicants. However, few data are available to assess the maternal risks of gestational exposure by race and infant sex. To begin to address this data gap, we characterized associations between maternal urinary phthalate metabolites and birth outcomes among African American and white mothers from a southeastern U.S. population. We enrolled pregnant African American (n = 152) and white (n = 158) women with singleton live births between 18 and 22 weeks gestation. We measured phthalate metabolites (mono-n-butyl phthalate (MBP), monoisobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), monoethyl phthalate (MEP), monomethyl phthalate (MMP), and the sums of DEHP (ΣDEHP) and DBP (ΣDBP) metabolites) in up to two gestational urine specimens from mothers, and evaluated confounder-adjusted associations per natural log unit greater concentration with birth weight for gestational age z-score, small for gestational age (SGA; <10th %tile), preterm birth (PTB; <37 weeks gestation), and low birth weight (LBW; <2500 g). We also tested for interactions by maternal race and infant sex. We found that lower z-scores were associated with greater MiBP (β = −0.28; 95% CI: −0.54, −0.02) and MMP (β = −0.30; 95% CI: −0.52, −0.09) concentrations, while MEP interacted with race (p = 0.04), indicating an association among whites (β = −0.14; 95% CI: −0.28, 0.001) but not among African Americans (β = 0.05; 95% CI = −0.09, 0.19). Greater MiBP (OR = 2.82; 95% CI: 1.21, 6.56) and MEOHP (OR = 2.80; 95% CI: 1.05, 7.42) were associated with an overall higher SGA risk, greater MEHP was associated with higher SGA risk (p = 0.10) in whites (OR = 3.26 95% CI: 0.64, 16.56) but not in African Americans (OR = 0.71 95% CI: 0.07, 7.17), and the associations for MiBP (p = 0.02) and ΣDBP (p = 0.02) varied by infant sex. We detected interactions for PTB in which African Americans were at higher risk than whites for greater MiBP (p = 0.08) and MEP (p = 0.02) although lower risk for greater MEHP (p = 0.09). Greater MEP was associated with an overall higher LBW risk (OR = 1.33; 95% CI: 0.95, 1.86), and males were at higher risk than females with greater MBP (p = 0.002), MiBP (p = 0.02), MBzP (p = 0.01), MEP (p = 0.002), MMP (p = 0.09), and ΣDBP (p = 0.01) concentrations. Overall, our results suggest that gestational phthalate exposure is associated with adverse maternal birth outcomes, and that the effects vary by maternal race and infant sex.

Maternal urinary phthalate metabolites in relation to gestational diabetes and glucose intolerance during pregnancy

BackgroundPhthalates are common plasticizer chemicals that have been linked to glucose intolerance in the general population, but there is only limited research on their association with gestational diabetes (GDM). ObjectiveWe evaluated the association between 11 urinary phthalate metabolites and GDM, impaired glucose tolerance (IGT), and continuous blood glucose concentration during pregnancy in The Infant Development and Environment Study (TIDES). Based on prior study results, our primary analyses focused on monoethyl phthalate (MEP) in relation to our outcomes of interest. Study designWe used multi-variable logistic regression to examine the odds of GDM and IGT in relation to an interquartile-range (IQR) increase in natural log (ln)-transformed, specific gravity (SG)-adjusted first trimester (T1) and average of T1 and third trimester (T3) (“T1T3avg”) phthalate metabolite concentrations. We fit linear regression models to examine the percent change in blood glucose per IQR increase in ln-transformed, SG-adjusted T1 and T1T3avg phthalates. In sensitivity analyses, we examined interactions between exposure and race. We adjusted for maternal age, maternal body mass index, study center, race/ethnicity, parity, and gestational age at glucose testing. ResultsIn our sample of 705 pregnant women, we observed 60 cases of GDM, 90 cases of IGT, and an average GLT blood glucose of 113.6 ± 27.7 mg/dL. In our primary analysis, T1T3avg MEP was positively associated with GDM ([OR (95% CI) per IQR increase] T1T3avg MEP: 1.61 (1.10, 2.36)). In secondary analyses, most other phthalates were not found to be related to study outcomes, though some associations were noted. Sensitivity analyses indicated possible strong race-specific associations in Asians, though these results are based on a small sample size (n = 35). ConclusionIn alignment with our a priori selection, we documented an association between T1T3avg MEP and GDM. Additional phthalate metabolites were also found to be linked to glucose intolerance, with possible stronger associations in certain racial/ethnic subgroups. Given the prevalence of phthalate exposures and the growing evidence of associations with metabolic outcomes, future studies should continue to examine this question in diverse cohorts of pregnant women, particularly in those who may be at higher risk for GDM and IGT.

Erratum: “Associations between Repeated Measures of Maternal Urinary Phthalate Metabolites and Thyroid Hormone Parameters during Pregnancy”

Background:Maintaining thyroid homeostasis during pregnancy is essential for normal fetal growth and development. Growing evidence suggests that phthalates interfere with normal thyroid function. F...

Placental weight in relation to maternal and paternal preconception and prenatal urinary phthalate metabolite concentrations among subfertile couples

IntroductionPhthalates are known reproductive toxicants that reduce placental and fetal weight in experimental animal studies. Although phthalate exposure has been associated with reduced birth weight in humans, there is limited epidemiologic evidence on whether the placenta is also affected. ObjectiveTo assess whether maternal and paternal preconception and prenatal urinary phthalate metabolite concentrations are associated with placental weight, and the birth weight: placental weight (BW:PW) ratio among singletons conceived by subfertile couples. MethodsThe present analysis included 132 mothers and 68 fathers, and their corresponding 132 singletons recruited in an academic hospital fertility center in Boston, Massachusetts. Urinary concentrations of eleven phthalate metabolites were measured and averaged in multiple paternal (n = 196) and maternal (n = 596) preconception, and maternal prenatal (n = 328) samples. Placental weight and birth weight (grams) were abstracted from delivery records, and the BW:PW was calculated. We estimated the association of natural log-phthalate metabolite concentrations across windows of exposure with placental weight and the BW:PW ratio using multivariable linear regression models, adjusting for a priori covariates. ResultsIn adjusted models, each log-unit increase in paternal urinary concentrations of the sum of di-(2-ethylhexyl) phthalate (ΣDEHP) metabolites was associated with a 24 g (95% CI: −48, −1) decrease in placental weight. We also observed a significant negative association between maternal preconception monoethyl phthalate (MEP) metabolite concentrations and the BW:PW ratio (β = −0.26; 95%CI: −0.49, −0.04). Additionally, each log-unit increase in prenatal MEP metabolite concentrations was associated with a 24 g (95% CI: −41, −7) decrease in placental weight. ConclusionsOur results suggest that certain paternal and maternal urinary phthalate metabolites may affect placental weight and the BW:PW ratio. However, given the small sample size within a subfertile cohort and the novelty of these findings, more studies are needed to confirm the present results.