Monocarboxyisooctyl Phthalate Research Articles

Urinary concentrations of phthalate metabolites in relation to preeclampsia and other hypertensive disorders of pregnancy in the environmental influences on child health outcomes (ECHO) program

BackgroundPhthalate exposure may contribute to hypertensive disorders of pregnancy (HDP), including preeclampsia/eclampsia (PE/E), but epidemiologic studies are lacking. ObjectivesTo evaluate associations of pregnancy phthalate exposure with development of PE/E and HDP. MethodsUsing data from 3,430 participants in eight Environmental influences on Child Health Outcomes (ECHO) Program cohorts (enrolled from 1999 to 2019), we quantified concentrations of 13 phthalate metabolites (8 measured in all cohorts, 13 in a subset of four cohorts) in urine samples collected at least once during pregnancy. We operationalized outcomes as PE/E and composite HDP (PE/E and/or gestational hypertension). After correcting phthalate metabolite concentrations for urinary dilution, we evaluated covariate-adjusted associations of individual phthalates with odds of PE/E or composite HDP via generalized estimating equations, and the phthalate mixture via quantile-based g-computation. We also explored effect measure modification by fetal sex using stratified models. Effect estimates are reported as odds ratios (OR) with 95% confidence intervals (95% CIs). ResultsIn adjusted analyses, a doubling of mono-benzyl phthalate (MBzP) and of mono (3-carboxypropyl) phthalate (MCPP) concentrations was associated with higher odds of PE/E as well as composite HDP, with somewhat larger associations for PE/E. For example, a doubling of MCPP was associated with 1.12 times the odds of PE/E (95%CI 1.00, 1.24) and 1.02 times the odds of composite HDP (95%CI 1.00, 1.05). A quartile increase in the phthalate mixture was associated with 1.27 times the odds of PE/E (95%CI 0.94, 1.70). A doubling of mono-carboxy isononyl phthalate (MCiNP) and of mono-carboxy isooctyl phthalate (MCiOP) concentrations were associated with 1.08 (95%CI 1.00, 1.17) and 1.11 (95%CI 1.03, 1.19) times the odds of PE/E. Effect estimates for PE/E were generally larger among pregnancies carrying female fetuses. DiscussionIn this study, multiple phthalates were associated with higher odds of PE/E and HDP. Estimates were precise and some were low in magnitude. Interventions to reduce phthalate exposures during pregnancy may help mitigate risk of these conditions.

Measurement of 24 phthalate metabolites in 1st trimester urine samples: The MIREC study

Phthalates are non-persistent chemicals measured as metabolites in urine. Over time, new metabolites have been identified. In the original Maternal-Infant Research on Environmental Chemicals (MIREC) study (2008–2011), we measured 11 phthalate metabolites in first trimester urine samples. The goal of the present study was to develop a method to measure new metabolites, to increase the sensitivity for some previously measured metabolites, and to measure these new metabolites in biobanked urine samples from MIREC participants.Using Ultra Performance Liquid Chromatography with a tandem mass spectrometer, we developed a method to measure 24 metabolites from 10 different parent phthalates. Chromatographic interpretation of some of the di-iso-decyl phthalate metabolites (mono-(2-propyl-6oxoheptyl) phthalate (MOiDP), mono-(2,7-methyl-7-carboxyheptyl) phthalate (MCiNP), mono-(2-propyl-6-hydroxy-heptyl) phthalate (MHiDP)) and di-iso-nonyl phthalate metabolites (mono(oxo-isononyl) phthalate (MOiNP), mono(carboxy-isooctyl) phthalate (MCiOP), mono(hydroxy-isononyl) phthalate (MHiNP) and mono-isononyl phthalate (MiNP)) was challenging as these are complex isomeric mixtures.To validate and confirm our quantitation peaks, an assay using a high-resolution detection technique was developed on a Quadrupole Time-of-Flight (QToF) system. This system has a mass resolution of at least 0.005 amu, compared to 0.5 amu for the MS/MS detector. Using the QToF system, the distinction between an isomer and possible interference was achieved with the use of the exact mass.In about 1800 MIREC samples, mono-cyclo-hexyl phthalate (MCHP), mono-(7-carboxy-n-heptyl) phthalate (MCHpP), mono-iso-decyl phthalate (MiDP), and mono-n-octyl phthalate (MnOP) were rarely detected, while detection of MMP was improved. MCiOP, MiNP and MCiNP had to be reported semi-quantitatively.Given the complexity of isomeric mixtures of some phthalates, researchers must be careful in their determination of the analytes and the approach used in their quantification when generating biomonitoring data.This study produced biomonitoring data for a large population of pregnant people that can be used in risk assessment of phthalates. Future work will examine associations with birth and child outcomes.

Temporal trends in urinary concentrations of phenols, phthalate metabolites and phthalate replacements between 2000 and 2017 in Boston, MA

Endocrine disrupting chemicals (EDCs) can adversely affect human health and are ubiquitously found in everyday products. We examined temporal trends in urinary concentrations of EDCs and their replacements. Urinary concentrations of 11 environmental phenols, 15 phthalate metabolites, phthalate replacements such as two di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) metabolites, and triclocarban were quantified using isotope-dilution tandem mass spectrometry. This ecological study included 996 male and 819 female patients who were predominantly White/Caucasian (83 %) with an average age of 35 years and a BMI of 25.5 kg/m2 seeking fertility treatment in Boston, MA, USA. Patients provided a total of 6483 urine samples (median = 2, range = 1–30 samples per patient) between 2000 and 2017. Over the study period, we observed significant decreases (% per year) in urinary concentrations of traditional phenols, parabens, and phthalates such as bisphenol A (β: -6.3, 95 % CI: −7.2, −5.4), benzophenone-3 (β: -6.5, 95 % CI: −1.1, −18.9), parabens ((β range:-5.4 to −14.2), triclosan (β: -18.8, 95 % CI: −24, −13.6), dichlorophenols (2.4-dichlorophenol β: -6.6, 95 % CI: −8.8, −4.3); 2,5-dichlorophenol β: -13.6, 95 % CI: −17, −10.3), di(2-ethylhexyl) phthalate metabolites (β range: −11.9 to −22.0), and other phthalate metabolites including mono-ethyl, mono-n-butyl, and mono-methyl phthalate (β range: −0.3 to −11.5). In contrast, we found significant increases in urinary concentrations of environmental phenol replacements including bisphenol S (β: 3.9, 95 % CI: 2.7, 7.6) and bisphenol F (β: 6, 95 % CI: 1.8, 10.3), DINCH metabolites (cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester [MHiNCH] β: 20, 95 % CI: 17.8, 22.2; monocarboxyisooctyl phthalate [MCOCH] β: 16.2, 95 % CI: 14, 18.4), and newer phthalate replacements such as mono-3-carboxypropyl phthalate, monobenzyl phthalate, mono-2-ethyl-5-carboxypentyl phthalate and di-isobutyl phthalate metabolites (β range = 5.3 to 45.1), over time. Urinary MHBP concentrations remained stable over the study period. While the majority of biomarkers measured declined over time, concentrations of several increased, particularly replacement chemicals that are studied.

Associations between Prenatal Exposure to Phthalates and Features of the Metabolic Syndrome in Males from Childhood into Adulthood.

Phthalate metabolites are detectable within the majority of the population. Evidence suggests that a prenatal exposure to phthalates may be associated with the subsequent risks of obesity and elevated blood pressure. We hypothesised that a prenatal exposure to phthalates would lead to an increase in adverse cardiometabolic parameters through childhood and adulthood. The maternal serum phthalate measurements from the stored samples taken from Gen1 mothers at 18 and 34 weeks gestation were examined in relation to the cardiometabolic measures in 387 male offspring from the Raine Study. Data from the Gen2 follow-ups between 3 and 27 years were used. The primary outcomes were analysed longitudinally using linear mixed models for the repeated measures. Non-alcoholic fatty liver disease (NAFLD) was assessed at 17 years using logistic regression. A consistent positive relationship was observed between a prenatal exposure to mono-carboxy-iso-octyl phthalate (MCiOP) through adolescence into adulthood with systolic blood pressure. There were no other consistent cardiovascular associations. Mid-levels of prenatal exposures to Mono-n-butyl phthalate (MnBP) were associated with a greater incidence of NAFLD. Detectable Mono-3-carboxypropyl phthalate (MCPP) was associated with a lower serum HDL-C through late childhood into adulthood, while a higher prenatal exposure to mono-iso-butyl phthalate (MiBP), was associated with a higher LDL-C at 22 years of age. A mid-level prenatal exposure to mono-2-ethylhexyl phthalate (MEHP) metabolites was associated with higher insulin in adulthood, while a higher prenatal exposure to the sum of the Di-(2-ethyl-hexyl) phthalate (DEHP) and Di-iso-nonyl phthalate (DiNP) metabolites was associated with higher fasting serum glucose in adulthood. In conclusion, our study demonstrated that higher prenatal phthalate exposures to some phthalate metabolites was associated with some adverse metabolic profiles through adolescence into adulthood, although the consistent themes were limited to a few metabolites and the outcomes of systolic blood pressure, fasting insulin and glucose.

Association of phthalate exposure with low birth weight in couples conceiving naturally or via assisted reproductive technology in a prospective birth cohort

BackgroundFew studies have investigated the adverse effects of preconception phthalate (PAE) exposure on birth weight in couples receiving assisted reproductive technology (ART) compared to naturally conceived newborns. ObjectivesWe examined the association between parental preconception/prenatal urinary phthalate exposure and low birth weight (LBW) risk in couples who conceived using ART or naturally. MethodsFrom the Jiangsu Birth Cohort Study (China), we recruited 544 couples who conceived after infertility treatment and 940 couples who conceived naturally and gave birth to a singleton infant between November 2014 and December 2019. Seventeen metabolites of phthalate and three metabolites of phthalate alternatives were analyzed in parental spot urine samples. Clinical data were collected from medical records. We used generalized linear models, elastic net regression, Bayesian kernel machine regression, and quantile-based g-computation to examine the individual and joint effects of parental phthalate exposure on birth weight and LBW risk ratios (RR). ResultsThe relationship between parental phthalate exposure and birth weight was consistent between ART and natural conception. Maternal exposure to mono-ethyl phthalate and mono-carboxyisooctyl phthalate was associated with an increased risk of LBW in ART-conceived infants (RR = 1.27; 95 % confidence interval (CI): 1.03, 1.56; and RR = 1.31; 95 % CI: 1.03, 1.67, respectively). In contrast, in the spontaneously conceived infants, higher paternal prenatal concentrations of mono-benzyl phthalate and mono-carboxyisononyl phthalate were associated with a 40 % and 53 % increase in LBW risk, respectively. Exposure to PAE mixtures was associated with LBW in ART-conceived infants, with the effects primarily driven by di-ethyl phthalate, benzylbutyl phthalate, and di-isononyl phthalate metabolites. Sex-specific LBW was observed, with females appearing to be more susceptible than males. ConclusionsMaternal preconception and paternal prenatal exposure to phthalates were associated with increased risk of LBW in infants. Compared with natural conception, ART-conceived fetuses were more sensitive to PAE mixtures, which requires further attention.

Associations between repeated measures of urinary phthalate metabolites and biomarkers of oxidative stress in a rural agricultural cohort of children with asthma

Phthalate exposure is widespread, and studies suggest an adverse relationship with asthma morbidity, including some support for oxidative stress as an underlying pathophysiological mechanism. Urinary phthalate metabolites have been associated with biomarkers of oxidative stress, but data are few in children diagnosed with asthma. We used participant data from the Home Air in Agriculture Pediatric Intervention Trial (HAPI) to examine longitudinal relationships between phthalates and oxidative stress in a cohort of Latino children with asthma residing in an agricultural community. We used linear mixed-effects models to estimate associations between 11 urinary phthalate metabolites (and one summed measure of di-2-ethylhexyl phthalate (DEHP) metabolites, ∑DEHP) and two urinary biomarkers of oxidative stress: a biomarker of lipid peroxidation via measure of 8-isoprostane and a biomarker of DNA/RNA oxidative damage via combined measure of 8-hydroxydeoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), and 8-hydroxyguanine. Seventy-nine participants provided 281 observations. In covariate-adjusted models, we observed significant positive relationships between all phthalate metabolites and 8-isoprostane, effect sizes ranging from a 9.3 % (95 % CI: 4.2 %–14.7 %) increase in 8-isoprostane for each 100 % increase (i.e., doubling) of mono-(carboxy-isooctyl) phthalate (MCIOP), to a 21.0 % (95 % CI: 14.3 %–28.2 %) increase in 8-isoprostane for each doubling of mono-n-butyl phthalate (MNBP). For each doubling of mono-(carboxy-isononyl) phthalate (MCINP) and mono-ethyl phthalate (MEP), the DNA/RNA oxidative damage biomarker increased by 6.0 % (95 % CI: 0.2 %–12.2 %) and 6.5 % (95 % CI: 1.4 %–11.9 %), respectively. In conclusion, we provide unique data suggesting phthalate exposure is positively associated with oxidative stress in children with asthma. Our repeat measures provide novel identification of a consistent effect of phthalates on oxidative stress in children with asthma via lipid peroxidation. Confirmation in future studies of children with asthma is needed to enhance understanding of the role of phthalates in childhood asthma morbidity.

Exposure to Contemporary and Emerging Chemicals in Commerce among Pregnant Women in the United States: The Environmental influences on Child Health Outcome (ECHO) Program.

Prenatal chemical exposures can influence maternal and child health; however, few industrial chemicals are routinely biomonitored. We assessed an extensive panel of contemporary and emerging chemicals in 171 pregnant women across the United States (U.S.) and Puerto Rico in the Environmental influences on Child Health Outcomes (ECHO) Program. We simultaneously measured urinary concentrations of 89 analytes (103 total chemicals representing 73 parent compounds) in nine chemical groups: bactericides, benzophenones, bisphenols, fungicides and herbicides, insecticides, organophosphate esters (OPEs), parabens, phthalates/alternative plasticizers, and polycyclic aromatic hydrocarbons (PAHs). We estimated associations of creatinine-adjusted concentrations with sociodemographic and specimen characteristics. Among our diverse prenatal population (60% non-Hispanic Black or Hispanic), we detected 73 of 89 analytes in ≥1 participant and 36 in >50% of participants. Five analytes not currently included in the U.S. biomonitoring were detected in ≥90% of samples: benzophenone-1, thiamethoxam, mono-2-(propyl-6-carboxy-hexyl) phthalate, monocarboxy isooctyl phthalate, and monohydroxy-iso-decyl phthalate. Many analyte concentrations were higher among women of Hispanic ethnicity compared to those of non-Hispanic White women. Concentrations of certain chemicals decreased with the calendar year, whereas concentrations of their replacements increased. Our largest study to date identified widespread exposures to prevalent and understudied chemicals in a diverse sample of pregnant women in the U.S.

Exposure to prenatal phthalate mixtures and neurodevelopment in the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study

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

The effects of the phthalate DiNP on reproduction†.

Di-isononyl phthalate (DiNP) is a high molecular weight, general purpose, plasticizer used primarily in the manufacture of polymers and consumer products. It can be metabolized rapidly and does not bioaccumulate. The primary metabolite of DiNP is monoisononyl-phthalate (MiNP) and the secondary metabolites include three oxidative derivatives of DiNP, which have been identified mainly in urine: mono-oxoisononyl phthalate (MOINP or oxo-MiNP), mono-carboxyisooctyl phthalate (MCIOP, MCOP or cx-MiNP), and mono-hydroxyisononyl phthalate (MHINP or OH-MiNP). The secondary metabolites are very sensitive biomarkers of DiNP exposure while primary metabolites are not. As the usage of DiNP worldwide increases, studies evaluating its potential reproductive toxicity are becoming more prevalent in the literature. In studies on female animals, the researchers found that the exposure to DiNP appears to induce negative effects on ovarian function and fertility in animal models. Whether or not DiNP has direct effects on the uterus is still controversial, and the effects on human reproduction require much more research. Studies on males indicate that DiNP exposure has disruptive effects on male reproduction and fertility. Occupational studies also indicate that the exposure to DiNP might induce negative effects on male reproduction, but larger cohort studies are needed to confirm this. This review presents an overview of the literature regarding the reproductive effects of exposure to DiNP.

Exposure to environmental phthalates during preschool age and obesity from childhood to young adulthood

Obesity rates are increasing globally, and recent theories suggest that phthalates may contribute to obesity development. This longitudinal study aimed to investigate associations between environmental phthalate exposure during childhood and obesity, utilizing data from 100 participants from a Swedish birth cohort. The participants were followed repeatedly from birth and provided spot urine samples at 4 years. Weight and height were measured at ages 4, 8, 16 and 24 years, as well as additional anthropometric indices at 24 years. Urine samples were analysed for 10 phthalate metabolites using liquid chromatography tandem mass spectrometry. Generalized estimating equation models were performed to assess overall and age-specific associations between urinary phthalate concentrations and BMI groups; thin/normal weight vs overweight/obese. After adjustment for potential confounders, overall associations were observed for diisononyl phthalate (DiNP) metabolites mono(oxo-isononyl) phthalate (MOiNP) (OR per increase ng/ml: 1.18; 95% CI: 1.05, 1.33), mono(carboxy-isooctyl) phthalate (MCiOP) (OR: 1.06; 95% CI: 1.01, 1.11) and ∑DiNP (OR: 1.02; 95% CI:1.00, 1.04) and development of overweight/obesity up to age 24 years. Age-specific associations were observed for the same metabolites at 8, 16 and 24 years. Furthermore, linear regression analysis revealed associations between increased body fat % at age 24 years and MHiNP (β: 2.42; 95% CI: 0.44, 4.39), MOiNP (β: 2.32; 95% CI: 0.46, 4.18), MCiOP (β: 2.65; 95% CI: 0.41, 4.89) and ∑DiNP (β: 2.65; 95% CI: 0.52, 4.77). These findings suggest that DiNP exposure during preschool age may be associated with subsequent obesity, however these findings need to be corroborated by further research.

Prenatal phthalate, paraben, and phenol exposure and childhood allergic and respiratory outcomes: Evaluating exposure to chemical mixtures

BackgroundChemicals found in personal care products and plastics have been associated with asthma, allergies, and lung function, but methods to address real life exposure to mixtures of these chemicals have not been applied to these associations. MethodsWe quantified urinary concentrations of eleven phthalate metabolites, four parabens, and five other phenols in mothers twice during pregnancy and assessed probable asthma, aeroallergies, and lung function in their age seven children. We implemented Bayesian Profile Regression (BPR) to cluster women by their exposures to these chemicals and tested the clusters for differences in outcome measurements. We used Bayesian Kernel Machine Regression (BKMR) to fit biomarkers into one model as joint independent variables. ResultsBPR clustered women into seven groups characterized by patterns of personal care product and plastic use, though there were no significant differences in outcomes across clusters. BKMR showed that monocarboxyisooctyl phthalate and 2,4-dichlorophenol were associated with probable asthma (predicted probability of probable asthma per IQR of biomarker z-score (standard deviation) = 0.08 (0.09) and 0.11 (0.12), respectively) and poorer lung function (predicted probability per IQR = −0.07 (0.05) and −0.07 (0.06), respectively), and that mono(3-carboxypropyl) phthalate and bisphenol A were associated with aeroallergies (predicted probability per IQR = 0.13 (0.09) and 0.11 (0.08), respectively). Several biomarkers demonstrated positive additive effects on other associations. ConclusionsBPR and BKMR are useful tools to evaluate associations of biomarker concentrations within a mixture of exposure and should supplement single-chemical regression models when data allow.

Phthalate exposure in pregnant women with systemic lupus erythematous (SLE)

TPS 632: Health effects of flame retardants and plasticizers, Johan Friso Foyer, Floor 1, August 27, 2019, 3:00 PM - 4:30 PM Background: Environmental chemicals might contribute to the pathogenesis of autoimmune diseases in combination with established genetic factors. Phthalate exposure in pregnant women may influence fetal growth and birth outcomes. Hence, we assessed phthalate exposure in pregnant women with systemic lupus erythematous (SLE) and compared levels with nationally-representative and pregnant populations. Methods: Participants were 50 pregnant women from the New York City (NYC) sample of PROMISSE (2003-2010), a multi-ethnic/racial cohort designed to prospectively assess adverse pregnancy outcomes in SLE women with inactive or mild/moderate disease activity. We measured urinary concentrations of 21 phthalate metabolites during each trimester and compared median concentrations with 1) 15-to-50 year-old women in the National Health and Nutrition Examination Survey (NHANES) 2003-2010; and 2) a contemporary population-based cohort of pregnant women in NYC (n=240). Results: Intraclass correlations for three measurements across pregnancy varied between r=0 [mono-carboxy isooctyl phthalate (mCIOP)] and r=0.57 [mono-n-butyl-phthalate (mBP)]. Mono-(3-carboxypropyl) phthalate (mCPP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (mECPP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), mCIOP, and mono-carboxy isononyl phthalate (mCINP) were detected in all pregnant women, comparable to NHANES. Metabolites of di-(2-propylheptyl) phthalate (DPHP) and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) were detected in 4-55% of participant. Compared to NHANES, pregnant women with SLE had higher first trimester concentration of mono-(2-ethylhexyl) phthalate (MEHP) [median=3.9 ng/mL interquartile range (IQR)=6.0 vs 2.5 ng/mL, IQR=5.45], mono-isobutyl phthalate (mIBP) (median=12.8 vs 7.6 ng/mL), mono-isononyl phthalate (mINP) (median=2.7 vs. 0.87 ng/mL), and mCIOP (median=14.9 vs 6.9 ng/mL). Concentrations of other phthalate metabolites were comparable between groups. Pregnant women with SLE had higher phthalate levels than the NYC cohort. Conclusions: Pregnant women with SLE had higher concentrations of certain phthalate metabolites than controls. This cross-sectional analysis cannot rule out that SLE might influence phthalate metabolism. Sociodemographic and lifestyles factors might also explain the results; therefore, further investigation is needed.

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.

Prenatal and childhood exposure to phthalates and motor skills at age 11 years

BackgroundPrevious reports suggest that prenatal phthalate exposure is associated with lower scores on measures of motor skills in infants and toddlers. Whether these associations persist into later childhood or preadolescence has not been studied. MethodsIn a follow up study of 209 inner-city mothers and their children the concentrations of mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monomethyl phthalate (MEP), mono-carboxy-isooctyl phthalate (MCOP), and four di-2-ethylhexyl phthalate metabolites (ΣDEHP) were measured in spot urine sample collected from the women in late pregnancy and from their children at ages 3, 5, and 7 years. The Bruininks-Oseretsky Test of Motor Proficiency short form (BOT-2) was administered at child age 11 to assess gross and fine motor skills. ResultsThe total number of children included in the study was 209. Of the 209 children, 116(55.5%) were girls and 93 were (45%) boys. Among girls, prenatal MnBP(b=−2.09; 95%CI: [−3.43, −0.75]), MBzP (b=−1.14; [95%CI: −2.13, −0.14]), and MiBP(b=−1.36; 95%CI: [−2.51, −0.21] and MEP(b=−1.23 [95%CI: −2.36, −0.11]) were associated with lower total BOT-2 composite score. MnBP (b= –1.43; 95% CI: [–2.44, –0.42]) was associated with lower fine motor scores and MiBP(b = –0.56; 95% CI: [–1.12, –0.01]) and MEP (b = –0.60; 95% CI: [–1.14, −0.06])was associated with lower gross motor scores. Among boys, prenatal MBzP (b = –0.79; 95% CI: [–1.40, −0.19]) was associated with lower fine motor composite score.The associations between MEP measured at age 3 and the BOT-2 gross motor, fine motor and total motor score differed by sex. In boys, there was an inverse association between ΣDEHP metabolites measured in childhood at ages 3 (b = –1.30; 95% CI: [–2.34, −0.26]) and 7 years (b = –0.96; 95% CI: [–1.79, −0.13]), and BOT-2 fine motor composite scores. ConclusionsHigher prenatal exposure to specific phthalates was associated with lower motor function among 11- year old girls while higher postnatal exposure to ΣDEHP metabolites was associated with lower scores among boys. As lower scores on measures of motor development have been associated with more problems in cognitive, socioemotional functioning and behavior, the findings of this study have implications related to overall child development.

Prenatal Exposure to Select Phthalates and Phenols and Associations with Fetal and Placental Weight among Male Births in the EDEN Cohort (France).

Background:The placenta performs crucial physiological functions to ensure normal fetal development. Few epidemiological studies investigated placental weight sensitivity to phthalates and phenols.Objective:Our goal was to explore whether maternal exposure to select phthalates and phenols is associated with changes in placental weight at birth and in placental–to–birth weight ratio (PFR).Methods:Placental weight and birth weight were available for 473 mother–son pairs in the EDEN (Etude des Déterminants pré et postnatals du développement et de la santé de l’Enfant) cohort for whom 9 phenols (4 parabens, 2 dichlorophenols, triclosan, benzophenone-3, bisphenol A) and 11 phthalate metabolites were measured in spot urine samples collected between weeks 23 and 29 of gestation. We used adjusted Elastic Net penalized regression models (ENET) to select biomarkers associated with placental weight, birth weight and PFR. Unpenalized effect estimates were then obtained by fitting linear regression models simultaneously adjusted for the ENET-selected biomarkers and a priori chosen confounders.Results:The multipollutant ENET model for placental weight retained four biomarkers: triclosan and monocarboxy-isononyl phthalate (MCNP), which were negatively associated with placental weight, and benzophenone-3 and the sum of parabens, which were positively associated with this outcome. The ENET model for PFR retained two phthalate metabolites [MCNP and monocarboxy-isooctyl phthalate (MCOP)], which were negatively associated with this outcome.Discussion:The positive association between the sum of parabens and placental weight was consistent with results of a previous study among 49 male births. Our results provide preliminary evidence of possible associations between other compounds such as triclosan, benzophenone-3, MCNP, and MCOP and both placental weight and PFR. These associations were not reported in previous studies and should be seen as hypothesis generating. Studies relying on repeated assessments of exposure in prospective mother–child cohorts are needed to substantiate the plausibility of the hypotheses generated by our results. https://doi.org/10.1289/EHP3523

Prepubertal and Pubertal Endocrine-Disrupting Chemical Exposure and Breast Density among Chilean Adolescents.

During puberty, mammary tissue undergoes rapid development, which provides a window of heightened susceptibility of breast composition to the influence of endogenous and exogenous hormones. Exposure to endocrine-disrupting chemicals (EDC) may affect breast development and composition and the risk of developing breast cancer in adulthood. We evaluated the associations between breast density and urinary concentrations of phenols and phthalates collected at Tanner 1 (B1) and Tanner 4 (B4) in 200 Chilean girls. Total breast volume (BV), fibroglandular volume (FGV), and percent dense breast (%FGV) were evaluated at B4 using dual X-ray absorptiometry. Generalized estimating equations were used to analyze the association between concentrations of EDC biomarkers across puberty and breast density. The geometric mean %FGV was 7% higher among girls in the highest relative to the lowest tertile of monocarboxyisooctyl phthalate [1.07; 95% confidence interval (CI), 1.01-1.14]. Monoethyl phthalate concentrations at B4 were positively associated with FGV (highest vs. lowest tertile: 1.22; 95% CI, 1.06-1.40). Bisphenol A displayed a U-shaped association with FGV; girls in the middle tertile had at least 10% lower FGV than girls in the lowest or highest tertiles. Monocarboxyisononyl phthalate showed a nonlinear association with BV. No other statistically significant associations were observed. Our results suggest that the developing breast tissue is susceptible to select EDCs during childhood and adolescence. This study may spur further investigations into environmental influences on breast development during puberty and how shifts in pubertal breast density track through the life course to modify breast cancer risk.

Prenatal high molecular weight phthalates and bisphenol A, and childhood respiratory and allergic outcomes.

The prevalence of asthma and allergy is increasing in US children. In utero exposure to chemicals used in personal care products and plastics may contribute to increase in these diseases. We quantified urinary concentrations of eight phthalate metabolites and bisphenol A in mothers twice during pregnancy in 1999-2000 in Salinas, California. We assessed probable asthma, aeroallergies, eczema, and spirometry in their children at age 7, and measured T helper 1 and T helper 2 cells in blood at ages 2, 5, and 7 (N=392). We employed Bayesian model averaging to select confounders from additional biomarkers measured in this population and controlled for them in logistic and linear regressions. Monocarboxyisooctyl phthalate was associated with increased odds for probable asthma (odds ratio: 1.54, 95% CI: 1.12, 2.12), and with lower forced expiratory volume in one second (β: -0.09L, 95% CI: -0.15, -0.03) and forced expiratory flow from 25% to 75% of forced vital capacity (β: -7.06L/s, 95% CI: -11.04, -2.90). Several other associations were attenuated in final models that controlled for additional biomarkers. Monocarboxyisooctyl phthalate was associated with lower respiratory health after controlling for related chemical exposure, which suggests that confounding by multiple chemical exposures should be considered in future research.

Distribution and predictors of urinary concentrations of phthalate metabolites and phenols among pregnant women in the Healthy Start Study

BackgroundPhthalates and phenols are suspected endocrine disrupting chemicals that may adversely impact fetal outcomes following in utero exposure. Understanding predictors of exposure to phthalates and phenols during the prenatal period is important. MethodsWe measured urinary concentrations of 15 phthalate metabolites and 11 phenols in 446 pregnant women enrolled in the Healthy Start pre-birth cohort. Creatinine-adjusted geometric means (GM) for each urinary biomarker were compared across categories of potential sociodemographic and dietary predictors. To assess the independent relationship between each significant food group predictor and biomarker we used multivariable models, adjusted for sociodemographic predictors. ResultsThe phthalate metabolites with the highest concentrations were monoethyl phthalate (GM: 41.1µg/g creatinine) and monocarboxyisooctyl phthalate (GM: 20.5µg/g creatinine). Benzophenone-3 (GM: 124.6µg/g creatinine) and methyl paraben (GM: 119.9µg/g creatinine) were the phenols with the highest concentrations. Concentrations of the metabolites of di-n-butyl phthalate and di(2-ethylhexyl) phthalate were significantly higher in younger, unmarried or unemployed mothers, those who were overweight or obese, those with lower educational attainment, or those of minority race/ethnicity (p-values < 0.05). Metabolites of di-n-butyl phthalate concentrations were 18% lower in those who consumed milk ≥ 7 times per week (95% CI: 30–4%). Benzophenone-3 and triclosan concentrations were significantly higher in older, married, or employed mothers, those with normal body mass index, higher educational attainment, higher household income, or who were non-Hispanic white (p-values < 0.05). Benzophenone-3 concentrations were 62% higher in those who consumed seafood ≥ 5 times per month (95% CI: 16–127%). ConclusionsWe observed differences in urinary concentrations of phthalates and phenol biomarkers by sociodemographic predictors in an ethnically diverse cohort of pregnant women. These results and future analyses from this prospective cohort will help inform targeted interventions to reduce exposure to these potential endocrine disrupting chemicals during pregnancy.

Maternal and early life exposure to phthalates: The Plastics and Personal-care Products use in Pregnancy (P4) study

Phthalates are a group of chemicals found in a number of consumer products; some of these phthalates have been shown to possess estrogenic activity and display anti-androgenic effects. While a number of biomonitoring studies of phthalates in pregnant women and infants have been published, there is a paucity of data based on both multiple sampling periods and in different matrices. Phthalate metabolites were measured in 80 pregnant women and their infants in Ottawa Canada (2009–2010) in urine, meconium and breast milk collected at various time periods pre- and post-parturition. At least 50% of the women had at least one urine sample greater than the limit of detection (LOD) for the various phthalate metabolites, with the exception of mono-n-octyl phthalate (MnOP), mono-isononyl phthalate (MiNP) and mono(carboxy-isooctyl) phthalate (MCiOP). Four major clusters of maternal urinary metabolites were identified. Among infants (n=61), the following metabolites were rarely (< 10%) detected: mono-cyclohexyl phthalate (MCHP), mono-isononyl phthalate (MiNP), mono-methyl phthalate (MMP), and mono-n-octyl phthalate (MnOP). While mono-benzyl phthalate (MBzP), mono-3-carboxypropyl phthalate (MCPP), MEHHP, and MEOHP were frequently detected in maternal urines at any time point, these metabolites were rarely detected in breast milk. Maternal urinary concentrations of MEP and the DEHP metabolites were higher in samples collected during pregnancy than postnatally. No statistically significant differences were observed in infant's urinary phthalate concentrations between breast-fed and bottle-fed infants. Significant correlations were observed between maternal urinary MEHHP (r=0.35), MEOHP (r=0.35) and MEP (r=0.37) collected at <20weeks gestation with levels in meconium and between MBzP (r=0.78) and MEP (r=0.56) in maternal and infant urine collected 2–3months after birth. These results suggest at least some maternal-fetal-infant transfer of phthalates and that meconium may be a useful matrix for measuring in utero exposure to phthalates.

Urinary Phthalate Metabolite Concentrations and Reproductive Outcomes among Women Undergoing in Vitro Fertilization: Results from the EARTH Study.

Background:Evidence from both animal and human studies suggests that exposure to phthalates may be associated with adverse female reproductive outcomes.Objective:We evaluated the associations between urinary concentrations of phthalate metabolites and outcomes of assisted reproductive technologies (ART).Methods:This analysis included 256 women enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2004–2012) who provided one to two urine samples per cycle before oocyte retrieval. We measured 11 urinary phthalate metabolites [mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), monoethyl phthalate (MEP), monocarboxyisooctyl phthalate (MCOP), monocarboxyisononyl phthalate (MCNP), and mono(3-carboxypropyl) phthalate (MCPP)]. We used generalized linear mixed models to evaluate the association of urinary phthalate metabolites with in vitro fertilization (IVF) outcomes, accounting for multiple IVF cycles per woman.Results:In multivariate models, women in the highest as compared with lowest quartile of MEHP, MEHHP, MEOHP, MECPP, ΣDEHP (MEHP + MEHHP + MEOHP + MECPP), and MCNP had lower oocyte yield. Similarly, the number of mature (MII) oocytes retrieved was lower in the highest versus lowest quartile for these same phthalate metabolites. The adjusted differences (95% CI) in proportion of cycles resulting in clinical pregnancy and live birth between women in the fourth versus first quartile of ΣDEHP were –0.19 (–0.29, –0.08) and –0.19 (–0.28, –0.08), respectively, and there was also a lower proportion of cycles resulting in clinical pregnancy and live birth for individual DEHP metabolites.Conclusions:Urinary concentrations of DEHP metabolites were inversely associated with oocyte yield, clinical pregnancy, and live birth following ART.Citation:Hauser R, Gaskins AJ, Souter I, Smith KW, Dodge LE, Ehrlich S, Meeker JD, Calafat AM, Williams PL, for the EARTH Study Team. 2016. Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: results from the EARTH study. Environ Health Perspect 124:831–839; http://dx.doi.org/10.1289/ehp.1509760