Low Molecular Weight Phthalate Metabolites Research Articles

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.

Association of urinary concentrations of phthalate metabolites with quinolinic acid among women: a potential link to neurological disorders

Background/Aim: Quinolinic acid (QA), a neuroactive metabolite produced during tryptophan degradation, is implicated in the pathogenesis of several neurological disorders. Phthalates are structurally similar to QA, and exposure to phthalates has demonstrated increased QA production and excretion in rodent studies. We recently showed that very high exposure to dibutyl phthalate was associated with higher concentrations of urinary QA in men. However, no human studies examined the associations between background (low) phthalate exposures and QA. We examine the associations of urinary phthalate metabolite concentrations with QA. Methods: Female participants (N=126) who participated in a prospective cohort study at a Fertility Center in Boston provided 758 urine samples (273 during pregnancy and 485 during non-pregnancy). Concentrations of 11 phthalate metabolites and QA in urine were measured. We used multivariable linear mixed effect models to estimate the percent change in urinary QA concentrations associated with a doubling (100%) of phthalate metabolite concentration, and evaluated whether there was effect modification by pregnancy.Results: Women’s mean (standard deviation) age was 34.2 (4.0) years with a body mass index of 23.5 (3.7) kg/m2. The women were primarily Caucasian (92%), had ≥a college degree (98%), and none were current smokers. In multivariable-adjusted models, the percent change in urinary QA concentrations was significantly higher for each doubling of several urinary phthalate metabolite concentrations. For example, each doubling of DBP metabolites was associated with a 13.7% (95%CI: 10.6, 16.9) higher QA. Associations between the low molecular weight phthalate metabolites and QA were stronger among samples collected during pregnancy as compared to non-pregnancy.Conclusions: Urinary concentrations of several phthalate metabolites were positively associated with QA among women. These findings, along with the known neurotoxicity of QA, warrant the need to examine whether QA concentrations may serve as a pathway for the adverse neurodevelopment outcomes found in children’s health studies.

Association of urinary concentrations of phthalate metabolites with quinolinic acid among women: A potential link to neurological disorders

BackgroundQuinolinic acid (QA), a neuroactive metabolite produced during tryptophan degradation, is implicated in the pathogenesis of several neurological disorders. Phthalates are structurally similar to QA, and exposure to phthalates has demonstrated increased QA production and excretion in rodent studies. We recently showed that very high exposure to dibutyl phthalate was associated with higher concentrations of urinary QA in men. However, no human studies examined the associations between background (low) phthalate exposures and QA. ObjectivesTo examine the associations of urinary concentrations of phthalate metabolites with QA. MethodsFemale participants (N = 126) who participated in a prospective cohort study at the Massachusetts General Hospital Fertility Center provided 758 urine samples (273 during pregnancy and 485 during non-pregnancy). Concentrations of 11 phthalate metabolites and QA in urine were measured. We used multivariable linear mixed effect models to estimate the percent change in urinary QA concentrations associated with a doubling (100%) of urinary phthalate metabolite concentration, and evaluated whether there was effect modification by pregnancy status. ResultsWomen’s mean (standard deviation) age was 34.2 (4.0) years with a body mass index of 23.5 (3.7) kg/m2. The women were primarily Caucasian (92%), had at least a college degree (98%), and none were current smokers. Pairwise Spearman correlations between concentrations for phthalate metabolites and QA measured in the same urine samples ranged from 0.36 for MEHP to 0.68 for dibutyl phthalate (DBP) metabolites. In multivariable-adjusted models, the percent change in urinary QA concentrations was significantly higher for each doubling of several urinary phthalate metabolite concentrations. For example, each doubling of DBP metabolites was associated with a 13.7% (95%CI: 10.6, 16.9)% higher QA. Associations between the low molecular weight phthalate metabolites and QA were stronger among samples collected during pregnancy as compared to non-pregnancy samples from the same women. ConclusionsUrinary concentrations of several phthalate metabolites were positively associated with QA among women. These findings, along with the known neurotoxicity of QA, warrant the need to examine whether QA concentrations may serve as a pathway for the adverse neurodevelopment outcomes found in children’s health studies.

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 prenatal environmental phenol and phthalate biomarkers with respiratory and allergic diseases among children aged 6 and 7 years

BackgroundPrenatal environmental phenol and phthalate exposures may alter immune or inflammatory responses leading to respiratory and allergic disease. ObjectivesWe estimated associations of prenatal environmental phenol and phthalate biomarkers with respiratory and allergic outcomes among children in the Mount Sinai Children's Environmental Health Study. MethodsWe quantified urinary biomarkers of benzophenone-3, bisphenol A, paradichlorobenzene (as 2,5-dichlorophenol), triclosan, and 10 phthalate metabolites in third trimester maternal samples and assessed asthma, wheeze, and atopic skin conditions via parent questionnaires at ages 6 and 7 years (n = 164 children with 240 observations). We used logistic regression to estimate covariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) per standard deviation difference in natural log biomarker concentrations and examined effect measure modification by child's sex. ResultsAssociations of prenatal 2,5-dichlorophenol (all outcomes) and bisphenol A (asthma outcomes) were modified by child's sex, with increased odds of outcomes among boys but not girls. Among boys, ORs for asthma diagnosis per standard deviation difference in biomarker concentration were 3.00 (95% CI: 1.36, 6.59) for 2,5-dichlorophenol and 3.04 (95% CI: 1.38, 6.68) for bisphenol A. Wheeze in the past 12 months was inversely associated with low molecular weight phthalate metabolites among girls only (OR: 0.27, 95% CI: 0.13, 0.59) and with benzophenone-3 among all children (OR: 0.65, 95% CI: 0.44, 0.96). ConclusionsPrenatal bisphenol A and paradichlorobenzene exposures were associated with pediatric respiratory outcomes among boys. Future studies may shed light on biological mechanisms and potential sexually-dimorphic effects of select phenols and phthalates on respiratory disease development.

Variability of urinary phenols and phthalate metabolites in school-age children of 5 European countries

Introduction: Improvement in exposure assessment and reduction of measurement error remains an important challenge in studies evaluating the potential health effects of non-persistent pollutants. We assessed the between-day and -season variability of 7 phenols (4 parabens, bisphenol-A, benzophenone-3, and triclosan) and 8 phthalate metabolites (4 di-2-ethylhexyl phthalate metabolites, mono-benzyl phthalate and 3 low molecular weight phthalate metabolites) in school-age children. Methods: We collected all the first morning and bedtime voids during 1 week in 2 different seasons of 152 children aged 6-9 years of age from 5 European birth cohorts. We analyzed non-persistent pollutants in 4 consecutive days’ pools (first morning + bedtime) and in the 2 weekly pools. All compounds were analyzed using liquid chromatography–mass spectrometry with limits of quantification ranging from 0.2 to 2.0ng/mL. We calculated intraclass-correlation coefficient (ICC) of the 4 consecutive days to assess between-day variability and of the 2 weekly pools to assess between-season variability. Results: Geometric mean concentrations ranged from 0.14ng/mL for n-butyl paraben to 61.3ng/mL for the low molecular mono-ethyl phthalate. Among phenols, bisphenol-A presented the lowest ICCs (between-day: 0.52, between-season: 0.18) whereas benzophenone-3 presented the highest ICCs (between-day: 0.87, between-season: 0.57). Among phthalates, the ICCs for between-day variability ranged from 0.57 for mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) to 0.67 for mono-iso-butyl phthalate (MiBP) and for seasonal variability from 0.51 for monoethyl phthalate (MEP) to 0.73 for mono-2-ethylhexyl phthalate (MEHP). Conclusions: This study suggests that phenols, except benzophenone-3, have higher between-day and seasonal variability than phthalate metabolites. Results from this study will serve to characterize the degree of exposure misclassification when using fewer biomarker measurements in the larger cohorts.

Early life Phthalate Exposure and Obesity and Cardiometabolic Traits in Childhood.

Introduction: Phthalates are industrial chemicals with endocrine disrupting properties. Human evidence on the effects of early life phthalate exposure on obesity and cardiovascular risks is limited to a few cross-sectional studies. We evaluated the associations between early life phthalate exposure with offspring obesity and cardiometabolic risk factors in 500 mother-child pairs from the RHEA pregnancy cohort in Crete, Greece. Methods: Seven phthalate metabolites were measured in spot urine samples collected from mothers (1st trimester) and their children at 4 years of age. We calculated the sum of DEHP metabolites (MEHP, MEHHP, and MEOHP) and combined high and low molecular-weight phthalate metabolites as ΣHMWPm (ΣDEHPm and MBzP) and ΣLMWPm (MEP, MiBP, and MnBP) respectively. We measured child weight, height, waist circumference, skinfold thicknesses, blood pressure (BP) and blood levels of lipids and C-reactive protein (CRP) at 4 and 6 years. Adjusted associations were obtained via multivariable regression analyses. Results: DEHP exposure during pregnancy was associated with higher CRP (β=0.41 mg/dL; 95% CI: 0.21, 0.61) at 4 years of age but was not associated with child adiposity measures at 4 and 6 years of age. Higher levels of ΣHMWPm at 4 years corresponded with 2.46 mm greater waist circumference and 8.07 mm greater sum of skinfolds gain during follow up only in girls (p for interaction <0.05). Similarly, ΣHMWPm at 4 years was associated with lower BMI z-scores in boys (β= -0.37; 95% CI: -0.70, -0.03) and with higher BMI z-scores in girls at 6 years (β= 0.56; 95% CI: 0.06, 1.07; p for sex interaction = 0.001). Phthalate exposure in pregnancy or childhood was not associated with child blood levels of lipids or blood pressure. Conclusions: Our findings suggest that early life phthalate exposure may affect child growth and adiposity in a sex-specific manner.

Longitudinal Associations of Phthalate Exposures During Childhood and Body Size Measurements in Young Girls.

Phthalates are environmental chemicals that may play a role in the development of obesity. Few studies have investigated longitudinal associations between postnatal phthalate exposures and subsequent anthropometric measurements in children. We collected data as part of The Breast Cancer and Environment Research Program at three US sites. A total of 1,239 girls, aged 6-8 years, were enrolled in 2004-2007. We categorized baseline phthalate exposures, assessed from creatinine-corrected urinary concentrations of low-molecular weight phthalate metabolites, as low, <78; medium, 78 to <194; and high, ≥194 μg/g creatinine and of high-molecular weight phthalates as low, <111; medium, 111-278; and high, ≥278 μg/g creatinine. Anthropometric measurements were collected through 2012 (n = 1,017). Linear mixed effects regression estimated how baseline low and high-molecular weight phthalate concentrations related to changes in girls' body mass index (BMI), height, and waist circumference at ages 7-13 years. Low-molecular weight phthalates were positively associated with gains in BMI and waist circumference. Predicted differences in BMI and waist circumference between girls with high versus low concentrations of low-molecular weight phthalates increased from 0.56 (95% confidence interval [CI]: -0.02, 1.1) to 1.2 kg/m (95% CI: 0.28, 2.1) and from 1.5 (95% CI: -0.38, 3.3) to 3.9 cm (95% CI: 1.3, 6.5), respectively. High-molecular weight phthalates were negatively associated with height but only among girls who were normal weight at baseline (BMI ≤ 85th percentile). Phthalates, specifically low-molecular weight phthalates, have small but detectable associations with girls' anthropometric outcomes. Low-molecular weight phthalates showed stronger associations than other types of phthalates.

Associations of urinary 5-methyl-2′-deoxycytidine and 5-hydroxymethyl-2′-deoxycytidine with phthalate exposure and semen quality in 562 Chinese adult men

5-methyl-2′-deoxycytidine (5mdC) and 5-hydroxymethyl-2′-deoxycytidine (5hmdC), products of DNA methylation and hydroxymethylation processes, have been detected previously in human urine, but their associations with environmental chemicals or healthy outcomes are unclear. The present investigation explored the associations between urinary 5mdC and 5hmdC with phthalate exposure and semen quality. We assessed semen parameters including sperm concentration, motility, and morphology, before measuring urinary 5mdC, 5hmdC and 13 phthalate metabolites among 562 subfertile men from Nanjing, China. Urinary 5mdC and 5hmdC were positively associated with the levels of low molecular weight phthalate metabolites (Low-MWP), high molecular weight phthalate metabolites (High-MWP), and the sum of all phthalate metabolites (ΣPAEs), respectively. Urinary 5mdC was associated with below-reference sperm concentration (odds ratios for increasing quartiles=1.0, 2.2, 3.0, 2.0; p for trend =0.02), sperm motility (1.0, 1.1, 1.9, 1.3; p for trend =0.05), and sperm morphology (1.0, 1.4, 2.3, 1.5; p for trend =0.05). Sperm concentration was associated with the highest quartile of urinary 5hmdC [odds ratio=1.9 (95% CI: 1.1, 3.6)]. Our findings showed significant associations between urinary 5mdC and 5hmdC with phthalate metabolites and semen parameters, which suggested urinary 5mdC and 5hmdC may be promising biomarkers in future epidemiological studies.

Exposure to Bisphenol A and Phthalates during Pregnancy and Ultrasound Measures of Fetal Growth in the INMA-Sabadell Cohort.

Background:Prenatal exposure to bisphenol A (BPA) and phthalates may affect fetal growth; however, previous findings are inconsistent and based on few studies.Objectives:We assessed whether prenatal exposure to BPA and phthalates was associated with fetal growth in a Spanish birth cohort of 488 mother–child pairs.Methods:We measured BPA and eight phthalates [four di(2-ethylhexyl) phthalate metabolites (DEHPm), mono-benzyl phthalate (MBzP), and three low-molecular-weight phthalate metabolites (LMWPm)] in two spot-urine samples collected during the first and third trimester of pregnancy. We estimated growth curves for femur length (FL), head circumference (HC), abdominal circumference (AC), biparietal diameter (BPD), and estimated fetal weight (EFW) during pregnancy (weeks 12–20 and 20–34), and for birth weight, birth length, head circumference at birth, and placental weight.Results:Overall, results did not support associations of exposure to BPA or DEHPm during pregnancy with fetal growth parameters. Prenatal MBzP exposure was positively associated with FL at 20–34 weeks, resulting in an increase of 3.70% of the average FL (95% CI: 0.75, 6.63%) per doubling of MBzP concentration. MBzP was positively associated with birth weight among boys (48 g; 95% CI: 6, 90) but not in girls (–27 g; 95% CI: –79, 25) (interaction p-value = 0.04). The LMWPm mono-n-butyl phthalate (MnBP) was negatively associated with HC at 12–20 pregnancy weeks [–4.88% of HC average (95% CI: –8.36, –1.36%)].Conclusions:This study, one of the first to combine repeat exposure biomarker measurements and multiple growth measures during pregnancy, finds little evidence of associations of BPA or phthalate exposures with fetal growth. Phthalate metabolites MBzP and MnBP were associated with some fetal growth parameters, but these findings require replication.Citation:Casas M, Valvi D, Ballesteros-Gomez A, Gascon M, Fernández MF, Garcia-Esteban R, Iñiguez C, Martínez D, Murcia M, Monfort N, Luque N, Rubio S, Ventura R, Sunyer J, Vrijheid M. 2016. Exposure to bisphenol A and phthalates during pregnancy and ultrasound measures of fetal growth in the INMA-Sabadell cohort. Environ Health Perspect 124:521–528; http://dx.doi.org/10.1289/ehp.1409190

Age and sex-specific relationships between phthalate exposures and obesity in Chinese children at puberty.

ObjectiveTo examine the age and sex-specific associations of urine levels of six mono-phthalates with body size and fat distribution in Chinese children at puberty.Materials and MethodsFour hundred and ninety-three school-aged children (247 boys, 246 girls) were recruited. Obesity related anthropometric indices were measured and body fat proportion (BF%) was calculated. Spot urine samples were collected and phthalate monoesters were detected by an API 2000 electrospray triple quadrupole mass spectrometer (ESI-MS/MS). Associations between phthalate exposure and overweight/obesity measures and their trends were examined by multiple linear regression and Logistic regression analyses, respectively.ResultsDi-2-ethylhexyl phthalate (DEHP) metabolites and monobutyl phthalate (MBP) were found to be the most detectable chemicals. In 8–10 years (yrs) group, concentrations of MEHP and MBP were significantly higher in girls than those in boys. However, concentrations of all phthalate monoesters, except for MEP and MEHP, in 11–13 yrs boys were significantly higher than those in girls. After adjusting for confounders including puberty onset, urinary concentrations of MBP and sum of low molecular-weight phthalate metabolites (∑LMP) were positively associated with boys' obesity in a concentration-effect manner, while concentrations of MEHP, MEHHP and sum of DEHP metabolites (∑MEHP) were negatively associated with girls' obesity. Associations between phthalate exposure levels and BMI z-score changes were age- and sex-specific in school-age children.ConclusionThere are age and sex-specific concentration-effect associations between phthalate exposure and fat distribution in Chinese children. Urinary phthalate levels in 11–13 yrs boys were about 30 percent higher than those in girls, and ∑MEHP levels in younger boys (<10 yrs) were significantly higher than those in elder boys (>10 yrs). Associations were positive for MBP and ∑LMP with both BMI z-score and fat distribution in boys >10 years of age, and negative for ∑MEHP with fat distribution in girls <10 years of age.

Prenatal phthalate exposure and performance on the Neonatal Behavioral Assessment Scale in a multiethnic birth cohort

We investigated the relationship between prenatal maternal urinary concentrations of phthalate metabolites and neonatal behavior in their 295 children enrolled in a multiethnic birth cohort between 1998 and 2002 at the Mount Sinai School of Medicine in New York City. Trained examiners administered the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) to children within 5 days of delivery. We measured metabolites of 7 phthalate esters in maternal urine that was collected between 25 and 40 weeks’ gestation. All but two phthalate metabolites were over 95% detectable. We summed metabolites on a molar basis into low and high molecular weight phthalates. We hypothesized the existence of sex-specific effects from phthalate exposure a priori given the hormonal activity of these chemicals. Overall we found few associations between individual phthalate metabolites or their molar sums and most of the BNBAS domains. However, we observed significant sex-phthalate metabolite interactions ( p < 0.10) for the Orientation and Motor domains and the overall Quality of Alertness score. Among girls, there was a significant linear decline in adjusted mean Orientation score with increasing urinary concentrations of high molecular weight phthalate metabolites ( B = −0.37, p = 0.02). Likewise, there was a strong linear decline in their adjusted mean Quality of Alertness score ( B = −0.48, p < 0.01). In addition, boys and girls demonstrated opposite patterns of association between low and high molecular weight phthalate metabolite concentrations and motor performance, with some indication of improved motor performance with increasing concentration of low molecular weight phthalate metabolites among boys. This is the first study to report an association between prenatal phthalate exposure and neurological effects in humans or animals, and as such requires replication.