Phthalate Biomarker Concentrations Research Articles

Gestational phthalate exposure and behavioral problems in preschool-aged children with increased likelihood of autism spectrum disorder

BackgroundExperimental studies have shown associations between gestational phthalate exposure and behavioral problems among offspring; however, epidemiological evidence is still mixed. This study aims to investigate whether gestational phthalate exposure is associated with behavioral problems in preschool-aged children. MethodsParticipants include 178 mother-child pairs from MARBLES (Markers of Autism Risk in Babies – Learning Early Signs), a cohort with high familial likelihood of autism spectrum disorder (ASD). We quantified 14 phthalate metabolites in multiple maternal urine samples collected during the 2nd and 3rd trimesters. Preschool behavior problems were assessed using the Child Behavioral Checklist (CBCL), a standardized instrument for evaluating behavior problems of children aged 1.5–5 years. To examine associations of CBCL scores with both individual phthalate biomarker concentrations and their mixture, we used negative binomial regression and weighted quantile sum regression. ResultsOverall, maternal phthalate biomarker concentrations were not associated with child behavior problems. Monoisobutyl phthalate (MiBP) concentrations were inversely associated with child anxious/depressed symptoms and somatic complaints. Mono-hydroxy-isobutyl phthalate (MHiBP) and monobenzyl phthalate (MBzP) were also inversely associated with somatic complaints. When assessing trimester-specific associations, more behavior problems were associated with the 2nd trimester biomarker concentrations: mono(3-carboxypropyl) phthalate (MCPP) and monocarboxyisononyl phthalate (MCNP) were positively associated with somatic complaints. All associations became non-significant after false discovery rate correction. No association between a mixture of phthalates and CBCL scores was found. ConclusionsOur study observed no clear evidence of gestational phthalate exposure on child behavior problems. However, our findings based on the biomonitoring assessment of multiple samples per participant could improve our understanding of gestational phthalate exposure in association with behavior problems in preschool-aged children.

Year-to-year variation in phthalate metabolites in the Midlife Women's Health Study.

Humans are widely exposed to phthalates, which are metabolized in the body and excreted in urine. Phthalate metabolites are excreted within hours of exposure, making urinary phthalate biomarker concentrations highly variable. The goal of this study was to characterize the long-term variability in phthalate biomarker concentrations in women across the midlife transition and to identify factors that may be associated with increased variability in those phthalate biomarker concentrations by analyzing longitudinal urinary phthalate metabolite data from the Midlife Women's Health Study (2006-2015). A total of 741 women were enrolled in the study for a period of up to 4 years, during which they each provided 2-4 urine samples per year over 4 consecutive weeks that were pooled for analysis (1876 total pools). Nine phthalate metabolites were assessed individually and as molar sums representative of common compounds (all phthalates: ƩPhthalates; DEHP: ƩDEHP), exposure sources (plastics: ƩPlastic; personal care products: ƩPCP), and modes of action (anti-androgenic: ƩAA). Phthalate metabolites were analyzed by quartile using generalized linear models. In addition, the impact of explanatory variables (race, annual family income, and type of work) on phthalate quartile was examined using ordinal logistic regression models. Phthalate biomarker concentrations are highly variable among midlife women over time, and annual sampling may not be sufficient to fully characterize long-term exposure.

Early pregnancy phthalates and replacements in relation to fetal growth: The human placenta and phthalates study

BackgroundPregnant persons are exposed ubiquitously to phthalates and increasingly to chemicals introduced to replace phthalates. In early pregnancy, exposure to these chemicals may disrupt fetal formation and development, manifesting adverse fetal growth. Previous studies examining the consequences of early pregnancy exposure relied on single spot urine measures and did not investigate replacement chemicals. ObjectiveCharacterize associations between urinary phthalate and replacement biomarkers in early pregnancy and fetal growth outcomes. MethodsAnalyses were conducted among 254 pregnancies in the Human Placenta and Phthalates Study, a prospective cohort with recruitment 2017–2020. Exposures were geometric mean concentrations of phthalate and replacement biomarkers quantified in two spot urine samples collected around 12- and 14-weeks of gestation. Outcomes were fetal ultrasound biometry (head and abdominal circumferences, femur length, estimated fetal weight) collected in each trimester and converted to z-scores. Adjusted linear mixed effects (single-pollutant) and quantile g-computation (mixture) models with participant-specific random effects estimated the difference, on average, in longitudinal fetal growth for a one-interquartile range (IQR) increase in individual (single-pollutant) or all (mixture) early pregnancy phthalate and replacement biomarkers. ResultsMono carboxyisononyl phthalate and the sums of metabolites of di-n-butyl, di-iso-butyl, and di-2-ethylhexyl phthalate were inversely associated with fetal head and abdominal circumference z-scores. A one-IQR increase in the phthalate and replacement biomarker mixture was inversely associated with fetal head circumference (β: -0.36 [95% confidence interval: -0.56, −0.15]) and abdominal circumference (−0.31 [-0.49, −0.12]) z-scores. This association was mainly driven by phthalate biomarkers. ConclusionsUrine concentrations of phthalate biomarkers, but not replacement biomarkers, in early pregnancy were associated with reductions in fetal growth. Though the clinical implications of these differences are unclear, reduced fetal growth contributes to excess morbidity and mortality across the lifecourse. Given widespread global exposure to phthalates, findings suggest a substantial population health burden resulting from early pregnancy phthalate exposure.

Associations of early life phthalate exposures with adolescent lipid levels and insulin resistance: The HOME Study.

Early-life phthalate exposures may disrupt metabolic processes; however few prospective studies have assessed whether these associations extend to cardiometabolic outcomes during adolescence. Among 183 mother-adolescent pairs in a prospective cohort study that enrolled pregnant women in Cincinnati, OH (2003-2006), we quantified nine phthalate metabolites in spot urine samples collected twice from mothers during pregnancy and up to seven times from children. At age 12 years, we assessed triglycerides, high-density (HDL) and low-density (LDL) lipoprotein cholesterol, insulin, and glucose from fasting serum samples and calculated homeostatic model assessment of insulin resistance (HOMA-IR). Using multiple informant models, we estimated covariate-adjusted associations between urinary phthalate concentrations at each time period and cardiometabolic biomarkers at age 12 years, including modification by child sex. Although most associations were weak or null, monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), and monobenzyl phthalate (MBzP) concentrations were generally associated with lower LDL at age 12 years. A 10-fold increase in 4- and 12-year MEP was associated with -15.3mg/dL (95% CI: 27.5, -3.13mg/dL) and -11.8mg/dL (-22.0, -1.51mg/dL) lower LDL, respectively. Discrepant associations were observed in females versus males: a 10-fold increase in 3-year MEP concentrations was associated with 12.0mg/dL (95% CI: 7.11, 31.1mg/dL) higher LDL levels in males and -30.4mg/dL (95% CI: 50.9, -9.8mg/dL) lower LDL levels in females. Some urinary phthalate concentrations were cross-sectionally associated with HOMA-IR. Early-life phthalate biomarker concentrations may be inversely associated with LDL during early adolescence in an exposure-period and sex-dependent manner.

Association between urinary phthalate biomarker concentrations and adiposity among postmenopausal women

BackgroundObesity is a leading risk factor for chronic diseases, potentially related to excess abdominal adiposity. Phthalates are environmental chemicals that have been suggested to act as obesogens, driving obesity risk. For the associations between phthalates and adiposity, prior studies have focused primarily on body mass index. We hypothesize that more refined measures of adiposity and fat distribution may provide greater insights into these associations given the role of central adiposity in chronic disease risk. ObjectivesTo evaluate associations between urinary phthalate biomarkers and both visceral and subcutaneous adipose tissue (VAT and SAT) among postmenopausal women enrolled in the Women's Health Initiative (WHI). MethodsWe included 1125 WHI participants with available, coincident measurements of urinary phthalate biomarkers (baseline, year 3) and VAT and SAT (baseline, year 3, year 6). VAT and SAT measurements were estimated from DXA scans. Multilevel mixed-effects models estimated the prospective associations between urinary phthalate biomarkers at baseline and VAT and SAT three years later. ResultsIn multivariable adjusted models, we observed positive associations between some phthalate biomarkers, including the sum of di-isobutyl phthalate (ΣDiBP) biomarkers, MCNP, and ΣDEHP, with VAT three years later. For example, we observed positive associations between concentrations of ΣDiBP and VAT (Q4 vs Q1 β = 7.15, 95% CI -1.76-16.06; Q3 vs Q1 β = 10.94, 95% CI 3.55–18.33). Associations were generally attenuated but remained significant after additional adjustment for SAT. MBzP was positively associated with SAT. Other phthalate biomarkers investigated (MEP, MCOP, MCPP, ΣDBP) were not significantly associated with VAT or SAT. DiscussionBased on robust measures of adiposity, this study provides supportive evidence that higher urinary concentrations of select phthalate compounds were associated with higher VAT levels over time in postmenopausal women. Efforts to replicate these findings are needed.

Dietary patterns and urinary phthalate exposure among postmenopausal women of the Women's Health Initiative

BackgroundPhthalates are endocrine-disrupting chemicals linked to a higher risk of numerous chronic health outcomes. Diet is a primary source of exposure, but prior studies exploring associations between dietary patterns and phthalate exposure are limited. ObjectivesWe evaluated the associations between dietary patterns and urinary phthalate biomarkers among a subset of postmenopausal women participating in the Women's Health Initiative (WHI). MethodsWe included WHI participants selected for a nested case-control study of phthalates and breast cancer (N = 1240). Dietary intake was measured via self-administered food frequency questionnaires at baseline and year-3. We used these data to calculate scores for alignment with the Dietary Approach to Stop Hypertension (DASH), alternative Mediterranean (aMed), and Dietary Inflammatory Index (DII) diets. We measured 13 phthalate metabolites and creatinine in 2–3 urine samples per participant collected over 3-years when all participants were cancer-free. We fit multivariable generalized estimating equation models to estimate the cross-sectional associations. ResultsDASH and aMed dietary scores were inversely associated with the sum of di(2-Ethylhexyl) phthalate (−6.48%, 95% CI -9.84, −3.00; −5.23%, 95% CI -8.73, −1.60) and DII score was positively associated (9.00%, 95% CI 5.04, 13.11). DASH and aMed scores were also inversely associated with mono benzyl phthalate and mono-3-carboxypropyl phthalate. DII scores were positively associated with mono benzyl phthalate and the sum of di-n-butyl phthalate. DiscussionHigher dietary alignment with DASH and aMed dietary patterns were significantly associated with lower concentrations of certain phthalate biomarkers, while an inflammatory diet pattern was associated with higher phthalate biomarker concentrations. These findings suggest that dietary patterns high in fruits, vegetables, and low-fat foods and low in processed foods may be useful in avoiding exposure to phthalates.

Determinants of urinary phthalate biomarker concentrations in pre- and perimenopausal women with consideration for race

Determinants of urinary phthalate biomarker concentrations in pre- and perimenopausal women with consideration for race

Determinants of urinary phthalate biomarker concentrations in pre- and perimenopausal women with consideration of race

Background/ObjectivesPhthalates are endocrine disruptors in consumer plastics and personal care products. Our objectives were to identify determinants of phthalate biomarkers in women during the hormonally-sensitive midlife period, and to consider differences between non-Hispanic White and Black women. MethodsWe used information from the Midlife Women's Health Study of pre- and peri-menopausal women from Baltimore, Maryland (enrolled 2006–2015). We collected sociodemographic/health information via baseline questionnaires or during clinic visits and measured nine phthalate metabolites in pools of 2–4 urines collected across one menstrual cycle. We calculated molar sums of metabolites to estimate exposure to di(2-ethylhexyl) phthalate (ΣDEHP), personal care product phthalates (ΣPCPs), and phthalates in plastics (ΣPlastics). Accounting for meaningful predictors from bivariable analyses, our multivariable linear regression models evaluated determinants of phthalate biomarkers in all women (n = 689), non-Hispanic White women only (n = 467), or non-Hispanic Black women only (n = 195). ResultsIn multivariable analyses of all women, those who were perimenopausal, widowed/divorced, non-Hispanic Black, with higher family income, with lower BMI, or who reported more frequent nausea had higher monoethyl phthalate (MEP) and ΣPCP. Non-Hispanic White women who were perimenopausal had lower mono-(3-carboxypropyl) phthalate (MCPP) and monobutyl phthalate (MBP), those who consume alcohol had higher mono-isobutyl phthalate (MiBP), and those with higher BMI had lower MEP and higher MCPP. Alternatively, widowed/divorced Black women had higher ΣDEHP, monobenzyl phthalate (MBzP), and ΣPlastics, whereas Black women with higher income had higher MEP and ΣPCP. Black women who described themselves as having “as much” physical activity as others or who reported a skin condition had lower MBzP and MCPP, respectively. ConclusionWe identified important determinants of phthalate biomarkers in midlife women and observed some differences by race. Future studies could consider reasons for these differences when developing interventions to reduce phthalate disparities and related health effects.

Serum PFAS and Urinary Phthalate Biomarker Concentrations and Bone Mineral Density in 12-19 Year Olds: 2011-2016 NHANES.

Per- and polyfluoroalkyl substances (PFAS) and phthalates are 2 families of environmental endocrine disruptors that may be associated with areal lower bone mineral density (aBMD). To examine associations between serum PFAS and urinary phthalate biomarker concentrations and their mixtures with aBMD Z-scores in adolescents. We examined serial cross-sectional data from male (n = 453) and female (n = 395) 12- to 19-year-old participants in the 2011 through 2016 National Health and Nutrition Examination Survey with measures of serum PFAS, urinary phthalate metabolites, and dual-energy X-ray absorptiometry aBMD Z-scores (total body less head). In sex-specific models, we used linear regression to examine associations of individual PFAS and phthalate biomarkers with aBMD Z-scores, and Bayesian kernel machine regression to examine the association of the overall PFAS/phthalate biomarker mixture with aBMD Z-scores. We replicated the analysis, stratifying by race/ethnicity. Participants were (mean ± SD) 15 ± 2.1 years of age. In males, each doubling of serum perfluorooctanoate (PFOA), perfluorooctane sulfonate, urinary mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate, and the overall PFAS/phthalate mixture was associated with a lower aBMD Z-score (eg, for PFOA: -0.24; 95% CI, -0.41 to -0.06). Serum PFOA and urinary MiBP were associated with higher aBMD Z-scores in females (eg, for PFOA: 0.09; 95% CI, -0.07 to 0.25). Findings did not differ by race/ethnicity. Certain PFAS and phthalates may be associated with reduced bone mineral density in adolescent males. Bone mineral density tracks across the life course, so if replicated in longitudinal cohorts, this finding may have implications for lifelong skeletal health.

Gestational and childhood phthalate exposures and adolescent body composition: The HOME study

BackgroundEarly life phthalate exposures may disrupt metabolism but results from human studies are inconsistent and few have examined body composition during adolescence. We investigated associations of gestational and childhood urinary phthalate biomarker concentrations with body composition at age 12 years. MethodsWe used data from 206 mother-child pairs in a prospective pregnancy and birth cohort enrolled in Cincinnati, OH from 2003 to 2006. We measured nine phthalate metabolites in spot urine samples collected twice from mothers during pregnancy and up to seven times from children at 1, 2, 3, 4, 5, 8, and 12 years. At age 12 years, we assessed fat and lean mass of the whole body and android and gynoid subregions, and visceral fat area with dual x-ray absorptiometry, and calculated android to gynoid %fat ratio and age- and sex-standardized fat and lean mass index z-scores. Using a multiple informant model, we estimated covariate-adjusted associations between urinary phthalate biomarker concentrations at each time period and outcomes at age 12 years. We assessed effect measure modification by child sex using stratified models. ResultsGenerally, urinary mono-benzyl phthalate (MBzP) concentrations were modestly associated with lower fat and lean mass. Each 10-fold increase in urinary MBzP concentrations during gestation and at ages 5 and 8 years was associated with a −0.34 (95%CI: −0.72, 0.05), −0.44 (95% CI: −0.83, −0.05), and −0.35 (95% CI: −0.71, 0.00) z-score difference in lean body mass index, respectively. Urinary monoethyl phthalate, mono-(3-carboxypropyl) phthalate, and summed di(2-ethylhexyl) phthalate metabolites were associated with greater lean mass at some exposure periods. Slightly weaker but similar patterns of association were found with other body composition measures; associations did not differ by child sex. ConclusionWhile most associations were weak, exposure to certain phthalates during gestation and childhood may be associated with adolescent body composition, particularly lean mass.

Prenatal maternal phthalate exposures and trajectories of childhood adiposity from four to twelve years.

Adiposity trajectories reflect dynamic process of growth and may predict later life health better than individual measures. Prenatal phthalate exposures may program later childhood adiposity, but findings from studies examining these associations are conflicting. We investigated associations between phthalate biomarker concentrations during pregnancy with child adiposity trajectories. We followed 514 mother-child pairs from the Mexico City PROGRESS cohort from pregnancy through twelve years. We measured concentrations of nine phthalate biomarkers in 2nd and 3rd trimester maternal urine samples to create a pregnancy average using the geometric mean. We measured child BMI z-score, fat mass index (FMI), and waist-to-height ratio (WHtR) at three study visits between four and 12 years of age. We identified adiposity trajectories using multivariate latent class growth modeling, considering BMI z-score, FMI, and WHtR as joint indicators of latent adiposity. We estimated associations of phthalates biomarkers with class membership using multinomial logistic regression. We used quantile g-computation to estimate the potential effect of the total phthalate mixture and assessed effect modification by sex. We identified three trajectories of child adiposity, a "low-stable", a "low-high", and a "high-high" group. A doubling of the sum of di (2-ethylhexyl) phthalate metabolites (ΣDEHP), was associated with 1.53 (1.08, 2.19) greater odds of being in the "high-high" trajectory in comparison to the "low-stable" group, whereas a doubling in di-isononyl phthalate metabolites (ΣDiNP) was associated with 1.43 (1.02, 2.02) greater odds of being in the "low-high" trajectory and mono (carboxy-isononyl) phthalate (MCNP) was associated with 0.66 (0.45, 97) lower odds of being in the "low-high" trajectory. No sex-specific associations or mixture associations were observed. Prenatal concentrations of urinary DEHP metabolites, DiNP metabolites, and MCNP, a di-isodecyl phthalate metabolite, were associated with trajectories of child adiposity. The total phthalate mixture was not associated with early life child adiposity.

Pregnancy exposure to phthalates and DNA methylation in male placenta - An epigenome-wide association study.

Exposure to phthalates during pregnancy may alter DNA methylation in the placenta, a crucial organ for the growth and development of the fetus. We studied associations between urinary concentrations of phthalate biomarkers during pregnancy and placental DNA methylation. We measured concentrations of 11 phthalate metabolites in maternal spot urine samples collected between 22 and 29 gestational weeks in 202 pregnant women. We analyzed DNA methylation levels in placental tissue (fetal side) collected at delivery. We first investigated changes in global DNA methylation of repetitive elements Alu and LINE-1. We then performed an adjusted epigenome-wide association study using IlluminaHM450 BeadChips and identified differentially methylated regions (DMRs) associated with phthalate exposure. Monobenzyl phthalate concentration was inversely associated with placental methylation of Alu repeats. Moreover, all phthalate biomarkers except for monocarboxy-iso-octyl phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate were associated with at least one DMR. All but three DMRs showed increased DNA methylation with increased phthalate exposure. The largest identified DMR (22 CpGs) was positively associated with monocarboxy-iso-nonyl phthalate and encompassed heat shock proteins (HSPA1A, HSPA1L). The remaining DMRs encompassed transcription factors and nucleotide exchange factors, among other genes. This is the first description of genome-wide modifications of placental DNA methylation in association with pregnancy exposure to phthalates. Our results suggest epigenetic mechanisms by which exposure to these compounds could affect fetal development. Of interest, four identified DMRs had been previously associated with maternal smoking, which may suggest particular sensitivity of these genomic regions to the effect of environmental contaminants.

Prenatal phthalates, gestational weight gain, and long-term weight changes among Mexican women

BackgroundPhthalates are endocrine disrupting chemicals that may influence weight status; however, few studies have considered weight gain during pregnancy and subsequent long-term weight changes in women. ObjectiveTo determine associations of prenatal phthalate exposure with maternal weight during pregnancy and through up to seven years post-delivery. MethodsWe analyzed 15 urinary phthalate biomarker concentrations during the 2nd and 3rd trimesters among 874 pregnant women enrolled in the Programming Research in Obesity, Growth Environment and Social Stress Study in Mexico City. We examined three time-specific maternal weight outcomes: gestational weight gain (between 2nd and 3rd trimesters), short-term weight (between 3rd trimester and 12 months post-delivery), and long-term weight (between 18 months and 6–7 years post-delivery). We used Bayesian Kernel Machine Regression (BKMR) to estimate associations for the total phthalate mixture, as well as multivariable linear mixed models for individual phthalate biomarkers. ResultsAs a mixture, 2nd trimester urinary phthalate biomarker concentrations were associated with somewhat lower gestational weight gain between the 2nd and 3rd trimesters (interquartile range, IQR, difference: −0.07 standard deviations, SD; 95% credible interval, CrI: −0.20, 0.06); multivariable regression and BKMR models indicated that this inverse association was primarily driven by mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP). Prenatal (2nd and 3rd trimesters) urinary phthalate mixture concentrations were positively associated with maternal weight change through 12 months postpartum (IQR difference: 0.11 SD; 95% CrI: 0.00, 0.23); these associations persisted from 18 months to 6–7 years follow-up (IQR difference: 0.07 SD; 95% CrI: 0.04, 0.10). Postpartum weight changes were associated with mono-3-carboxypropyl phthalate (MCPP) and MECPTP. ConclusionsPrenatal phthalate exposure was inversely associated with gestational weight gain and positively associated with long-term changes in maternal weight. Further investigation is required to understand how phthalates may influence body composition and whether they contribute to the development of obesity and other cardiometabolic diseases in women.

Associations of pregnancy phthalate concentrations and their mixture with early adolescent bone mineral content and density: The Health Outcomes and Measures of the Environment (HOME) study.

The developing fetus may be particularly susceptibility to environmental osteotoxicants, but studies of pregnancy phthalate exposures and childhood bone health are scarce. To examine relations of pregnancy phthalate exposure biomarkers with early adolescent bone mineral density (BMD) and bone mineral content (BMC) in a prospective birth cohort. We used data from 223 pregnant mothers and their children enrolled in a Cincinnati, OH area cohort from 2003 to 2006. We quantified monoethyl phthalate (MEP), monoisobutyl phthalate, monobutyl phthalate, monobenzyl phthalate, mono-(3-carboxypropyl) phthalate (MCPP), and four metabolites of di-2-ethylhexyl phthalate in maternal urine collected at 16 and 26weeks gestation, and calculated the average of creatinine-standardized concentrations. Using dual x-ray absorptiometry measures at age 12years, we calculated BMD and BMC Z-scores for six skeletal sites. In overall and sex-stratified models, we estimated covariate-adjusted associations per 2-fold increase in phthalate biomarker concentrations using linear regression, and estimated joint effects of the phthalate biomarkers mixture using Bayesian kernel machine regression (BKMR) and quantile g-computation. In single phthalate models, several biomarkers were positively associated with BMC and BMD. For example, each doubling of MEP and MCPP, 1/3rd distal radius BMD Z-score increased by 0.09 (95% CI: 0.01, 0.17) and 0.16 (95% CI: 0.01, 0.31), respectively. For phthalate mixtures, associations were generally U-shaped among males and positive-linear among females, using both statistical methods. Mixture associations were strongest with forearm sites: in BKMR models, increasing all biomarkers from the 50th to 90th percentile was associated with a 0.64 (95% CI: 0.01, 1.28) greater 1/3rd distal radius BMD Z-score in males, and a 0.49 (95% CI: -0.13, 1.10) greater ultradistal radius BMD Z-score in females. In this study, phthalate exposures during gestation were associated with increased BMD Z-scores in early adolescence, though further research is needed to determine implications for long-term skeletal health.

Maternal Phthalates Exposure and Blood Pressure during and after Pregnancy in the PROGRESS Study.

Background:Phthalate exposure is ubiquitous and may affect biological pathways related to regulators of blood pressure. Given the profound changes in vasculature during pregnancy, pregnant women may be particularly susceptible to the potential effects of phthalates on blood pressure.Objectives:We examined associations of phthalate exposure during pregnancy with maternal blood pressure trajectories from mid-pregnancy through 72 months postpartum.Methods:Women with singleton pregnancies delivering a live birth in Mexico City were enrolled during the second trimester (). Spot urine samples from the second and third trimesters were analyzed for 15 phthalate metabolites. Blood pressure and covariate data were collected over nine visits through 72 months postpartum. We used linear, logistic, and linear mixed models; latent class growth models (LCGMs); and Bayesian kernel machine regression to estimate the relationship of urinary phthalate biomarkers with maternal blood pressure.Results:As a joint mixture, phthalate biomarker concentrations during pregnancy were associated with higher blood pressure rise during mid-to-late gestation. With respect to individual biomarkers, second trimester concentrations of monobenzyl phthalate (MBzP) and di(2-ethylhexyl) phthalate biomarkers () were associated with higher third trimester blood pressure. Two trajectory classes were identified by LCGM, characterized by increasing blood pressure through 72 months postpartum (“increase–increase”) or decreased blood pressure through 18 months postpartum with a gradual increase thereafter (“decrease–increase”). Increasing exposure to phthalate mixtures during pregnancy was associated with higher odds of being in the increase–increase class. Similar associations were observed for mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and dibutyl phthalate () biomarkers. When specific time periods were examined, we observed specific temporal relationships were observed for , MECPTP, MBzP, and .Discussion:In our cohort of pregnant women from Mexico City, exposure to phthalates and phthalate biomarkers was associated with higher blood pressure during late pregnancy, as well as with long-term changes in blood pressure trajectories. https://doi.org/10.1289/EHP8562

The associations of phthalate biomarkers during pregnancy with later glycemia and lipid profiles

BackgroundPregnancy induces numerous cardiovascular and metabolic changes. Alterations in these sensitive processes may precipitate long-term post-delivery health consequences. Studies have reported associations between phthalates and metabolic complications of pregnancy, but no study has investigated metabolic outcomes beyond pregnancy. ObjectivesTo examine associations of exposure to phthalates during pregnancy with post-delivery metabolic health. DesignWe quantified 15 urinary phthalate biomarker concentrations during the second and third trimesters among 618 pregnant women from Mexico City. Maternal metabolic health biomarkers included fasting blood measures of glycemia [glucose, insulin, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR], % hemoglobin A1c (HbA1c%)] and lipids (total, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol, triglycerides), at 4–5 and 6–8 years post-delivery. To estimate the influence of the phthalates mixture, we used Bayesian weighted quantile sum regression and Bayesian kernel machine regression; for individual biomarkers, we used linear mixed models. ResultsAs a mixture, higher urinary phthalate biomarker concentrations during pregnancy were associated with post-delivery concentrations of plasma glucose (interquartile range [IQR] difference: 0.13 SD, 95%CrI: 0.05, 0.20), plasma insulin (IQR difference: 0.06 SD, 95%CrI: −0.02, 0.14), HOMA-IR (IQR difference: 0.08 SD, 95% CrI: 0.01, 0.16), and HbA1c% (IQR difference: 0.15 SD, 95%CrI: 0.05, 0.24). Associations were primarily driven by mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and the sum of dibutyl phthalate biomarkers (∑DBP). The phthalates mixture was associated with lower HDL (IQR difference: −0.08 SD, 95%CrI: −0.16, −0.01), driven by ∑DBP and monoethyl phthalate (MEP), and higher triglyceride levels (IQR difference: 0.15 SD, 95%CrI: 0.08, 0.22), driven by MECPTP and MEP. The overall mixture was not associated with total cholesterol and LDL. However, ∑DBP and MEP were associated with lower and higher total cholesterol, respectively, and MECPTP and ∑DBP were associated with lower LDL. ConclusionsPhthalate exposure during pregnancy is associated with adverse long-term changes in maternal metabolic health. A better understanding of timing of the exact biological changes and their implications on metabolic disease risk is needed.

Biomarkers of phthalates and inflammation: Findings from a subgroup of Women's Health Initiative participants.

Recent experimental work has shown that phthalates may increase inflammation. Prior research has not examined the role of exposure to phthalates in relation to inflammatory status among postmenopausal women who are at higher risk of developing inflammation-related chronic disorders. We aimed to examine the associations of urinary phthalate biomarker concentrations with circulating levels of c-reactive protein [CRP] and interleukin-6 [IL-6] among 443 postmenopausal women selected into a breast cancer case-control study nested within the Women's Health Initiative (WHI). A total of 13 phthalate metabolites were measured in urine samples provided at WHI enrollment from 1993 to 1998. We also measured baseline levels of CRP and IL-6 in these women's serum or plasma samples. Multivariable linear models were used to investigate the role of each phthalate biomarker in relation to CRP and IL-6, adjusting for potential confounding factors and specifically evaluating the role of BMI. In adjusted models we observed positive associations of monocarboxynonyl phthalate (MCNP) with CRP (β=0.092; 95% CI 0.026, 0.158) and IL-6 (β=0.108; 95% CI 0.013, 0.204). These positive associations were attenuated and non-significant, however, after further adjustment for body mass index (BMI). In contrast, we observed inverse associations of monoethyl phthalate (MEP) (β=-0.019; 95% CI -0.036, -0.001) and monobenzyl phthalate (MBzP) (β=-0.034; 95% CI -0.058, -0.010) with CRP levels only after adjustment for BMI. Other phthalate biomarkers examined were not significantly associated with either CRP or IL-6 levels. Overall, these results do not suggest an important role for phthalates in promoting an inflammatory response. Future prospective studies are warranted to improve understanding of these associations, particularly in clarifying the role of BMI.

Incidence of uterine leiomyoma in relation to urinary concentrations of phthalate and phthalate alternative biomarkers: A prospective ultrasound study

BackgroundNumerous studies suggest that some phthalates have adverse reproductive effects. However, literature on the association between phthalates and incidence of uterine leiomyomata (UL) is limited and inconsistent, with no existing prospective studies. ObjectivesWe examined the association of urinary concentrations of phthalate and phthalate alternative biomarkers with UL incidence. MethodsWe conducted a case-cohort analysis within a subgroup of 754 participants in the Study of the Environment, Lifestyle, and Fibroids (SELF), a prospective cohort of premenopausal Black women aged 23–35 years who were recruited during 2010–2012. We quantified fourteen phthalates and two phthalate alternative [1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH)] biomarkers in urine collected at baseline, 20 months, and 40 months. Transvaginal ultrasounds identified UL at baseline and every 20 months during 60 months of follow-up. We evaluated the individual biomarkers, molar sum of di(2-ethylhexyl) phthalate [ΣDEHP] and potency-weighted sum of anti-androgenic [WΣAA] biomarkers. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between biomarkers and UL incidence. We then used quantile g-computation to examine joint associations of multiple phthalate biomarkers with UL incidence. ResultsMost individual biomarkers showed weak-to-moderate inverse associations with UL incidence. HRs comparing highest vs. lowest quartiles of mono-isobutyl phthalate (MiBP) and mono-hydroxyisobutyl phthalate (MHiBP) concentrations were 0.63 (95% CI: 0.40, 1.01) and 0.61 (95% CI: 0.38, 0.96), respectively. Inverse associations for specific phthalates were stronger among women with BMI ≥ 30 kg/m2. HRs comparing detectable vs. nondetectable concentrations of DINCH biomarkers were 0.92 (95% CI: 0.62, 1.35) for cyclohexane-1,2-dicarboxylic acid mono hydroxyisononyl ester (MHNCH) and 0.68 (95% CI: 0.38, 1.18) for cyclohexane-1,2-dicarboxylic acid mono carboxyisoocytl ester (MCOCH). For the DEHP metabolite of mono(2-ethylhexyl) phthalate (MEHP), we observed weak-to-moderate positive associations. HRs comparing highest vs. lowest quartiles for MEHP and ΣDEHP were 1.29 (95% CI: 0.82, 2.06) and 0.96 (95% CI: 0.61, 1.50), respectively. In the mixtures analysis, the HR for a joint quartile increase in phthalate biomarker concentrations was 0.90 (95% CI: 0.73, 1.08). DiscussionIn this prospective ultrasound study of reproductive-aged Black women, urinary concentrations of phthalate and DINCH biomarkers were not appreciably associated with higher risk of UL, either individually or jointly.

Associations of prenatal exposure to phthalates with measures of cognition in 7.5-month-old infants

Background: Phthalates are endocrine disrupting chemicals found in consumer products. Prenatal exposure has been associated with adverse neurobehavior, but little is known about the influence on infant cognition. Methods: A visual recognition memory task was used to assess cognition in 239 7.5-month-old infants (122 females; 117 males) from a prospective cohort study. Phthalate metabolites were quantified in maternal urine from 16-18 gestational weeks and a pool of five urines collected across pregnancy. The cognitive task included familiarization trials (infant shown 2 identical images/stimuli) and test trials (infant shown a familiar image/stimulus paired with a novel one). During familiarization trials, average time looking at stimuli before looking away (measure of processing speed), and time to reach looking time criterion (measure of attention) were assessed. During test trials, proportion of time looking at the novel stimulus (measure of recognition memory) was assessed. Associations of monoethyl phthalate (MEP), sum of di(2-ethylhexyl) phthalate metabolites (∑DEHP), and sum of di(isononyl) phthalate metabolites (∑DINP) with each outcome were assessed using generalized linear models adjusted for multiple potential confounders. Infant sex was considered a potential effect modifier. Results: Mothers were mostly white and college educated. Phthalate biomarker concentrations were consistent with the U.S. general population. Each interquartile range (IQR) increase of ∑DEHP at 16-18 weeks was associated with a 5.2-second (95%CI=1.8,8.6) increase in time to reach looking time criterion in males but not females. An IQR increase in ∑DINP in the pooled sample was associated with a 1.0% (95%CI=-1.8,-0.3) decrease in novelty preference across both sexes and similarly associated with 16-18 week ∑DINP. MEP was not associated with cognition. None of the phthalate biomarkers were associated with information processing speed. Conclusion: Prenatal exposure to DEHP may be associated with poorer visual attention in males and DINP with poorer recognition memory in both sexes. ES007326;ES022848;ES028607;RD83543401;OD023272.

Temporal Trends of Exposure to Phthalates and Phthalate Alternatives in California Pregnant Women during 2007–2013: Comparison with Other Populations

Phthalates with potential adverse health effects are being replaced by other phthalates or phthalate alternatives. Little is known about temporal trends of phthalate exposure in pregnant women in the United States. We quantified 16 metabolites of eight phthalates and di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) in 656 urine samples collected from 192 California pregnant women in 2007-2013 during their second and third trimesters of pregnancy who participated in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) study. We used multiple regression to estimate least squares geometric means of phthalate biomarker concentrations and annual percent changes over the study period. Biomarker concentrations of diethyl phthalate (DEP) and three phthalates with known toxicity and adverse health effects (i.e., butyl benzyl phthalate [BBzP], dibutyl phthalate [DBP], di(2-ethylhexyl) phthalate [DEHP]) decreased, while those of di-isobutyl phthalate [DiBP], di-isononyl phthalate [DiNP], and di-n-octyl phthalate [DOP] increased in California pregnant women during our study period. To understand broad social forces that may influence temporal trends and geographic variations in phthalate exposure across countries, we compared our phthalate biomarker concentrations with those of other populations. We observed over a factor of 2 differences in exposure across countries for some phthalate biomarkers and between pregnant and nonpregnant women for DEP.