Urinary Phthalate Concentrations Research Articles

Urinary concentrations of phthalate and phthalate alternative metabolites and sperm DNA methylation: A multi-cohort and meta-analysis of men in preconception studies

Phthalates are ubiquitous pollutants in the environment; however, the mechanisms of phthalate-associated reproductive disorders in men are not fully understood. The aim of this study is to investigate associations between urinary phthalate metabolite concentrations and sperm DNA methylation. The study was conducted on 697 men from three prospective pregnancy cohorts: Longitudinal Investigation of Fertility and the Environment (LIFE) Study, Sperm Environmental Epigenetics and Development Study (SEEDS), and Environment and Reproductive Health (EARTH) Study. Eighteen phthalate and two phthalate alternative metabolites were quantified by mass spectrometry in preconception urinary samples and sperm DNA methylation was measured via Illumina EPIC Array (v1). Regional methylation analyses were conducted to identify cohort-specific loci associated with urinary phthalate metabolites. Models were adjusted for age, body mass index (BMI), race, smoking status, urinary creatinine/specific gravity, and analytical batch for phthalate measurements. The cohort-specific results were meta-analyzed using METAL. Participants had an average age of 30 years, most (79.6 %) of whom had BMI>25 kg/m2 and were non-smokers (90.1 %). A total of 7,979 differentially methylated regions (DMRs; 7,979 LIFE-specific DMRs, 72 SEEDS-specific DMRs, and 23 EARTH-specific DMRs) were associated with urinary MBzP, MiBP, MMP, MCNP, MCPP, MBP, and MCOCH. Meta-analysis identified fewer DMRs than cohort-specific models: 946 DMRs were associated with MBzP, 27 DMRs associated with MiBP, and 1 DMR associated with MEHP. The majority of cohort-specific and meta-analysis-derived DMRs displayed a positive association with phthalate metabolite concentrations and were enriched in genes associated with spermatogenesis, response to hormones and their metabolism, embryonic organ development and developmental growth. In conclusion, several preconception urinary phthalate metabolites were associated with increased DNA methylation patterns in sperm. These findings provide an epigenetic pathway by which environmental phthalate exposures can impact couples’ reproductive outcomes.

Phthalate Exposure and Pediatric Asthma: A Case Control Study Among Egyptian Children

Background: Phthalates, which are diesters of phthalic acid, are commonly used as plasticizers and additives in various consumer products. Several phthalates have been identified as substances of high concern. Exposure to phthalate esters (PAEs) has been linked to asthma in children, but the specific impacts of PAEs on asthmatic children were not well understood. Objective: The objective of this study was to compare urinary phthalate concentrations in asthmatic and non-asthmatic children and to identify potential sources of exposure as risk factors for asthma. Methods: A case control study was conducted for 100 Egyptian children aged 8-16 years (50 asthmatics and 50 healthy controls). Asthma was identified using GINA guidelines. Socio-demographic and probable risk factors were assessed, in addition to measuring phthalate levels in urine samples using high-performance liquid chromatography. Results and conclusion: Mean urinary Mono-methyl as well as Mono-benzyl levels were highly significant in asthmatic children compared to control group (895.26ng/ mL vs 548.55 ng/mL and 13.5 ng/mL vs 2.07 ng/mL respectively) (p= 0.001). The number of asthmatic children living in houses painted with non-plastic paint was significantly lower (P<0.05) than children living in houses painted with other paints. No association between floor type and asthma was reported. The frequent use of personal care products and plastic painting of walls were identified by multiple logistic regression analysis as the highly significant predictors of asthma in the studied subjects. The declared higher levels of urinary phthalate metabolites (Mono-methyl and Mono-benzyl) in Egyptian asthmatic children may reveal the probable risk of phthalate exposure in triggering bronchial asthma.

Associations of bisphenol and phthalate exposure and anti-Müllerian hormone levels in women of reproductive age

In women, exposure to endocrine disrupting chemicals might accelerate the depletion of the ovarian reserve and might be associated with accelerative reproductive aging and fertility. We examined the longitudinal associations of exposure to bisphenols and phthalates with anti-Müllerian hormone concentrations. Pregnant women of 18 years or older that resided in Rotterdam between 2002 and 2006 were eligible for participation in this longitudinal prospective cohort study. We measured urinary bisphenol and phthalate concentration at three time-points in pregnancy among 1405 women, of whom 1322 women had serum Anti-Müllerian Hormone (AMH) measurements 6 and/or 9 years postpartum. We performed linear regression models to assess the association of urinary bisphenol and phthalate metabolites with AMH after 6 and 9 years, and linear mixed-effect model to assess the association with AMH over time. Models were adjusted for sociodemographic and lifestyle factors. In our multivariable linear regression models we observed associations of higher urinary pregnancy-averaged mono-isobutyl phthalate (mIBP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and monobenzyl phthalate (mBzBP) with lower serum AMH after both 6 and 9 years. However, these associations did not remain after adjustment for multiple testing. No significant associations of bisphenol A with AMH were present in our study sample. In our linear mixed-effects models, higher mIBP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mEOHP, and mBzBP were associated with lower overall AMH levels (differences-0.07 (95% CI -0.13,-0.02),-0.09 (-0.15,-0.02),-0.08 (95% CI -0.14,-0.02), and-0.08 (-0.13,-0.03) μg/L per doubling in mIBP, mEHHP, mEOHP, and mBzBP respectively) (all False Discovery Rate adjusted p-values < 0.05). We identify decreases in indices of ovarian reserve in relationship to prenatal phthalate exposures. Studies are needed replicating our results among large multi-ethnic non-pregnant populations and assessing transgenerational effects of exposure on ovarian reserve. This study was supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development, the European Research Council, the Dutch Heart Foundation, the Dutch Diabetes Foundation, the European Union's Horizon 2020 Research and Innovation Program, the National Institutes of Health, Ansh Labs Webster, and the Royal Netherlands Academy of Arts and Sciences.

Urinary metabolite concentrations of phthalate and plasticizers in infancy and childhood in the UNC baby connectome project

IntroductionExisting evidence suggests that exposure to phthalates is higher among younger age groups. However, limited knowledge exists on how phthalate exposure, as well as exposure to replacement plasticizers, di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) and di-2-ethylhexyl terephthalate (DEHTP), change from infancy through early childhood. MethodsUrine samples were collected across the first 5 years of life from typically developing infants and young children enrolled between 2017 and 2020 in the longitudinal UNC Baby Connectome Project. From 438 urine samples among 187 participants, we quantified concentrations of monobutyl phthalate (MnBP), mono-3-carboxypropyl phthalate (MCPP), monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), and metabolites of di(2-ethylhexyl) phthalate (DEHP), diisonoyl phthalate (DiNP), DINCH and DEHTP. Specific gravity (SG) adjusted metabolite and molar sum concentrations were compared across age groups. Intraclass correlation coefficients (ICCs) were calculated among 122 participants with multiple urine specimens (373 samples). ResultsMost phthalate metabolites showed high detection frequencies (>80% of samples). Replacement plasticizers DINCH (58–60%) and DEHTP (>97%) were also commonly found. DiNP metabolites were less frequently detected (<10%). For some metabolites, SG-adjusted concentrations were inversely associated with age, with the highest concentrations found in the first year of life. ICCs revealed low to moderate reliability in metabolite measurements (ρ = 0.10–0.48) suggesting a high degree of within-individual variation in exposure among this age group. The first 6 months (compared to remaining age groups) showed an increased ratio of carboxylated metabolites of DEHP and DEHTP, compared to other common metabolites, but no clear age trends for DINCH metabolite ratios were observed. ConclusionMetabolites of phthalates and replacements plasticizers were widely detected in infancy and early childhood, with the highest concentrations observed in the first year of life for several metabolites. Higher proportions of carboxylated metabolites of DEHP and DEHTP in younger age groups indicate potential differences in metabolism during infancy.

Association between prenatal phthalate exposure and ano-genital indices among offsprings in an Israeli cohort

BackgroundIn-utero phthalate exposure was shown to be associated with shortened anogenital distance (AGD) in male newborns, but findings among female are inconsistent. While phthalate exposure among pregnant women in Israel is widespread, no study has examined the association with offspring AGD. The objective of the current study was to investigate the association between maternal phthalates urinary concentration and offspring AGD at time of delivery among a birth cohort in Israel. MethodsWe measured spot urinary concentration of monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-2-ethyl-5-hydroxyhexylphthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) among women presenting to the delivery room at Shamir Medical Center in Israel. Birthweight, length and AGD were measured in all newborns using a standardized protocol. Each AGD measurement was adjusted to weight (ano-genital index). Confounders included socio-demographic characteristics, comorbidities and obstetrical history. Univariate and multivariate analyses assessed the associations between phthalates, confounders and AGD. ResultsOverall, 193 mother and infant were analyzed. All newborns were born at term and had normal Apgar scores. Mean maternal age was 32 ± 4.7 years old. Mean birth weight and pregnancy week were 3183 ± 498 g and 39 ± 1.3, respectively. Median (IQR) urinary phthalate concentration adjusted to creatinine (ug/g) were 3.96 (2.2–6.6), 1.22 (0.7–2), 10.84 (7–20.4), 6.36 (3.3–11.2) and 0.64 (0.4–1.1) for MBP, MBzP, MECPP, MEHHP and MEOHP, respectively. Univariate comparison showed a significant association between higher than median MBzP concentration, higher Ano-Fourchetal index (AFI: 4.4 vs. 4.1, p = 0.037) and Ano-clitoral index (ACI: 11.5 vs. 10.4, p = 0.032) in infants. Total urinary phthalates concentration ≥26.25 μg/g was significantly associated with smaller penile width index (3.5 vs. 3.7, p = 0.022), higher ACI (11.6 vs. 10.3, p = 0.013) and a trend towards significance for higher AFI (4.3 vs. 4.1, p = 0.055). Following multivariate linear regression only PWI remained significantly associated with total phthalate urinary concentration. ConclusionsMaternal urinary phthalates concentration at delivery were not associated with female AGD, but total urinary phthalate concentration were inversely associated with penile width.

The associations between pre-conception urinary phthalate concentrations, the serum metabolome, and live birth among women undergoing assisted reproduction

BackgroundPhthalates are ubiquitous endocrine disruptors. Past studies have shown an association between higher preconception urinary concentrations of phthalate metabolites and lower fertility in women; however, the biological mechanisms remain unclear. Our exploratory study aimed to understand the metabolites and pathways associated with maternal preconception phthalate exposure and examine if any may underline the association between phthalate exposure and live birth using untargeted metabolomics. MethodsParticipants (n = 183) were part of the Environment and Reproductive Health (EARTH) study, a prospective cohort that followed women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital Fertility Center (2005–2016). On the same day, women provided a serum sample during controlled ovarian stimulation, which was analyzed for metabolomics using liquid chromatography coupled with high-resolution mass spectrometry and two chromatography columns, and a urine sample, which was analyzed for 11 phthalate metabolites using targeted approaches. We used multivariable generalized linear models to identified metabolic features associated with urinary phthalate metabolite concentrations and live birth, followed by enriched pathway analysis. We then used a meet-in-the-middle approach to identify overlapping pathways and features. ResultsMetabolic pathway enrichment analysis revealed 43 pathways in the C18 negative and 32 pathways in the HILIC positive columns that were significantly associated (p < 0.05) with at least one of the 11 urinary phthalate metabolites or molar sum of di-2-ethylhexyl phthalate metabolites. Lipid, amino acid, and carbohydrate metabolism were the most common pathways associated with phthalate exposure. Five pathways, tryptophan metabolism, tyrosine metabolism, biopterin metabolism, carnitine shuttle, and vitamin B6 metabolism, were also identified as being associated with at least one phthalate metabolite and live birth following IVF. ConclusionOur study provides further insight into the metabolites and metabolomics pathways, including amino acid, lipid, and vitamin metabolism that may underlie the observed associations between phthalate exposures and lower fertility in women.

Fetal bisphenol and phthalate exposure and early childhood growth in a New York City birth cohort

BackgroundExposure to endocrine-disrupting chemicals such as bisphenols and phthalates during pregnancy may disrupt fetal developmental programming and influence early-life growth. We hypothesized that prenatal bisphenol and phthalate exposure was associated with alterations in adiposity through 4 years. This associations might change over time. MethodsAmong 1091 mother–child pairs in a New York City birth cohort study, we measured maternal urinary concentrations of bisphenols and phthalates at three time points in pregnancy and child weight, height, and triceps and subscapular skinfold thickness at ages 1, 2, 3, and 4 years. We used linear mixed models to assess associations of prenatal individual and grouped bisphenols and phthalates with overall and time-point-specific adiposity outcomes from birth to 4 years. ResultsWe observed associations of higher maternal urinary second trimester total bisphenol and bisphenol A concentrations in pregnancy and overall child weight between birth and 4 years only (Beta 0.10 (95 % confidence interval 0.04, 0.16) and 0.07 (0.02, 0.12) standard deviation score (SDS) change in weight per natural log increase in exposure), We reported an interaction of the exposures with time, and analysis showed associations of higher pregnancy-averaged mono-(2-carboxymethyl) phthalate with higher child weight at 3 years (0.14 (0.06, 0.22)), and of higher high-molecular-weight phthalate, di-2-ethylhexyl phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-carboxymethyl) phthalate, and mono-(2-ethylhexyl) phthalate with higher child weight at 4 years (0.16 (0.04, 0.28), 0.15 (0.03, 0.27), 0.19 (0.07, 0.31), 0.16 (0.07, 0.24), 0.11 (0.03, 0.19)). Higher pregnancy-averaged high-molecular-weight phthalate, di-2-ethylhexyl phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, and mono-2(ethyl-5-oxohexyl) phthalate concentrations were associated with higher child BMI at 4 years (0.20 (0.05, 0.35), 0.20 (0.05, 0.35), 0.22 (0.06, 0.37), 0.20 (0.05, 0.34), 0.20 (0.05, 0.34)). For skinfold thicknesses, we observed no associations. DiscussionThis study contributes to the evidence suggesting associations of prenatal exposure to bisphenols and high-molecular-weight phthalates on childhood weight and BMI.

Associations between urinary phthalate concentrations and antral follicle count among women undergoing in vitro fertilization.

Phthalates are ubiquitously used in a variety of products and have an adverse effect on folliculogenesis. However, previous epidemiological studies on the associations between phthalate exposure and antral follicle count (AFC) produced conflicting results. The present study aimed to evaluate the associations between urinary phthalate metabolite concentrations and AFC among women undergoing in vitro fertilization (IVF). We collected 525 urine samples and measured 8 phthalate metabolites from IVF patients. Poisson regression models were conducted to evaluate the associations between phthalate metabolite concentrations and AFC. In addition, participants were stratified into a younger group (< 35 years) and an older group (≥ 35 years) to explore the potential effect modification by age. We also performed sensitivity analyses by restricting our analyses to only infertile women diagnosed with tubal factor infertility to test the robustness of the results. Significant positive associations were observed among urinary MBP, MEOHP and ∑PAEs concentrations and AFC after adjusting for age, BMI, year of study and infertility diagnosis. Compared with women in the first tertile, women in the third tertile of MBP and MEOHP had 7.02% (95% CI: 1.18%, 12.9%) and 8.84% (95% CI: 2.83%, 14.9%) higher AFC, respectively, and women in the second and third tertiles of ∑PAEs had 6.19% (95% CI: 0.37%, 12.0%) and 9.09% (95% CI: 3.22%, 15.0%) higher AFC, respectively. In addition, MBP, MEOHP and ∑PAEs also had significant positive associations with AFC in trend tests for dose-response. In the age-stratified analysis, we found a stronger relationship between phthalate metabolite concentrations and AFC among older women and an inverse association among younger women. We observed similar results in the sensitivity analyses. We found positive associations between phthalate exposure and AFC, which support the idea that phthalate exposure may accelerate primordial follicle recruitment and lead to higher AFC in women undergoing IVF. More studies are needed to better understand their relationships.

Longitudinal Associations between Prenatal Exposure to Phthalates and Steroid Hormones in Maternal Hair Samples from the SEPAGES Cohort.

We assessed phthalate-hormone associations in 382 pregnant women of the new-generation SEPAGES cohort (2014-2017, France) using improved exposure and outcome assessments. Metabolites from seven phthalate compounds and the replacement di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (≈21 samples/trimester). Metabolites from five steroid hormones were measured in maternal hair samples collected at delivery, reflecting cumulative levels over the previous weeks to months. Adjusted linear regression and Bayesian weighted quantile sum (BWQS) mixture models were performed. Each doubling in third-trimester urinary mono-benzyl phthalate (MBzP) concentrations was associated with an average increase of 13.3% (95% CI: 2.65, 24.9) for ∑cortisol, 10.0% (95% CI: 0.26, 20.7) for ∑cortisone, 17.3% (95% CI: 1.67, 35.4) for 11-dehydrocorticosterone, and 16.2% (95% CI: 2.20, 32.1) for testosterone, together with a suggestive 10.5% (95% CI: -1.57, 24.1) increase in progesterone levels. Each doubling in second-trimester urinary di-isononyl phthalate (DiNP) concentrations was inversely associated with testosterone levels (-11.6%; 95% CI: -21.6, -0.31). For most hormones, a nonsignificant trend toward a positive phthalate mixture effect was observed in the third but not in the second trimester. Our study showed that exposure to some phthalate metabolites, especially MBzP, may affect adrenal and reproductive hormone levels during pregnancy.

Cross-sectional associations between phthalates, phenols, and parabens with metabolic syndrome risk during early-to-mid adolescence among a cohort of Mexican youth

BackgroundEpidemiological studies on children and adults have linked toxicants from plastics and personal care products to metabolic disruption. Yet, the impact of endocrine-disrupting chemicals (EDCs) on adolescent metabolic syndrome (MetS) risk during early and mid-adolescence is unclear. MethodsTo examine the links between exposure to EDCs and MetS risk and its components, cross-sectional data from 344 Mexican youth in early-to-mid adolescence (10–17 years) were analyzed. Urinary biomarker concentrations of phthalates, phenol, and paraben analytes were measured from a single spot urine sample collected in 2015; study personnel obtained anthropometric and metabolic measures. We examined associations between summary phthalates and metabolites, phenol, and paraben analytes with MetS risk z-scores using linear regression, adjusted for specific gravity, sex, age, pubertal status, smoking, alcohol intake, physical activity level, and screen time. As a secondary aim, mediation analysis was conducted to evaluate the role of hormones in the association between summary phthalates with lipids and MetS risk z-scores. ResultsThe mean (SD) age was 13.2 (1.9) years, and 50.9% were female. Sex-stratified analyses revealed associations between summary phthalates and lipids ratio z-scores, including Σ DEHP [β = 0.21 (95% CI: 0.04, 0.37; p < 0.01)], phthalates from plastic sources (Σ Plastic) [β = 0.22 (95% CI: 0.05, 0.39; p < 0.01)], anti-androgenic phthalates (Σ AA) [β = 0.22 (95% CI: 0.05, 0.39; p < 0.01)], and individual phthalate metabolites (MEHHP, MEOHP, and MECPP) among males. Among females, BPA [β = 0.24 (95% CI: 0.03, 0.44; p < 0.05)] was positively associated with lipids ratio z-score and one phenol (2,5 DCP) [β = 0.09 (95% CI: 0.01, 0.18); p < 0.05)] was associated with increased waist circumference z-score. Results showed no evidence of mediation by hormone concentrations in the association between summary phthalates with lipids ratio or MetS risk z-scores. ConclusionHigher EDC exposure was positively associated with serum lipids during adolescence, particularly among males.

Prenatal exposure to multiple environmental chemicals and birth size.

Epidemiological studies addressing the combined effects of exposure to chemical mixtures at different stages of pregnancy on birth size are scarce. To evaluate the association between prenatal exposure to chemical mixtures and birth size. Our previous study repeatedly measured the urinary concentrations of 34 chemical substances among 743 pregnant women and identified three distinct clusters of exposed population and six dominant principal components of exposed chemicals in each trimester. In this study, we assessed the associations of these exposure profiles with birth weight, birth length, and ponderal index using multivariable linear regression. We found that compared with women in cluster 1 (lower urinary chemical concentrations), women in cluster 2 (higher urinary concentrations of metals, benzothiazole, benzotriazole, and some phenols), and women in cluster 3 (higher urinary concentrations of phthalates) were more likely to give birth to children with higher birth length [0.23 cm (95% CI: -0.03, 0.49); 0.29 cm (95%CI: 0.03, 0.54), respectively]. This association was observed only in 1st trimester. In addition, prenatal exposure to PC3 (higher benzophenones loading) was associated with reduced birth length across pregnancy [-0.07 cm (95% CI: -0.18, 0.03) in 1st and 2nd trimester; -0.13 cm (95% CI: -0.24, -0.03) in 3rd trimester]. Exposure to PC6 (higher thallium and BPA loading in 2nd trimester) was associated with increased birth length [0.15 cm (95% CI: 0.05, 0.26)]. Compared with other outcomes, associations of both clusters and PCs with birth length were stronger, and these associations were more pronounced in boys. Exposure to multiple chemicals simultaneously, the actual exposure situation of pregnant women, was associated with birth size, indicating that chemical mixtures should be taken more seriously when studying the health effects of pollutants.

The Association between Maternal Urinary Phthalate Concentrations and Blood Pressure in Pregnancy: A Systematic Review and Meta-Analysis.

Phthalates are commonly found in a wide range of environments and have been linked to several negative health outcomes. While earlier research indicated a potential connection between phthalate exposure and blood pressure (BP) during pregnancy, the results of these studies remain inconclusive. The objective of this meta-analysis was to elucidate the relationship between phthalate exposure and BP in pregnancy. A comprehensive literature search was carried out with PubMed, EMBASE, and Web of Science, and pertinent studies published up until 5 March 2023 were reviewed. Random-effects models were utilized to consolidate the findings of continuous outcomes, such as diastolic and systolic BP, as well as the binary outcomes of hypertensive disorders of pregnancy (HDP). The present study included a total of 10 studies. First-trimester MBP exposure exhibited a positive association with mean systolic and diastolic BP during both the second and third trimesters (β = 1.05, 95% CI: 0.27, 1.83, I2 = 93%; β = 0.40, 95% CI: 0.05, 0.74, I2 = 71%, respectively). Second-trimester monobenzyl phthalate (MBzP) exposure was positively associated with systolic and diastolic BP in the third trimester (β = 0.57, 95% CI: 0.01, 1.13, I2 = 0; β = 0.70, 95% CI: 0.27, 1.13, I2 = 0, respectively). Conversely, first-trimester mono-2-ethylhexyl phthalate (MEHP) exposure demonstrated a negative association with mean systolic and diastolic BP during the second and third trimesters (β = -0.32, 95% CI: -0.60, -0.05, I2 = 0; β = -0.32, 95% CI: -0.60, -0.05, I2 = 0, respectively). Additionally, monoethyl phthalate (MEP) exposure was found to be associated with an increased risk of HDP (OR = 1.12, 95% CI: 1.02, 1.23, I2 = 26%). Our study found that several phthalate metabolites were associated with increased systolic and diastolic BP, as well as the risk of HDP across pregnancies. Nevertheless, given the limited number of studies analyzed, additional research is essential to corroborate these findings and elucidate the molecular mechanisms linking phthalates to BP changes during pregnancy.

Longitudinal association of prepubertal urinary phthalate metabolite concentrations with pubertal progression among a cohort of boys

BackgroundEpidemiological studies have reported associations of anti-androgenic phthalate metabolite concentrations with later onset of male puberty, but few have assessed associations with progression. ObjectivesWe examined the association of prepubertal urinary phthalate metabolite concentrations with trajectories of pubertal progression among Russian boys. MethodsAt enrollment (ages 8–9 years), medical history, dietary, and demographic information were collected. At entry and annually to age 19 years, physical examinations including testicular volume (TV) were performed and spot urines collected. Each boy's prepubertal urine samples were pooled, and 15 phthalate metabolites were quantified by isotope dilution LC-MS/MS at Moscow State University. Metabolites of anti-androgenic parent phthalates were included: butylbenzyl (BBzP), di-n-butyl (DnBP), diisobutyl (DiBP), di(2-ethylhexyl) (DEHP) and diisononyl (DiNP) phthalates. We calculated the molar sums of DEHP, DiNP, and all AAP metabolites. We used group-based trajectory models (GBTMs) to identify subgroups of boys who followed similar pubertal trajectories from ages 8–19 years based on annual TV. We used multinomial and ordinal regression models to evaluate whether prepubertal log-transformed phthalate metabolite concentrations were associated with slower or faster pubertal progression trajectories, adjusting for covariates. Results304 boys contributed a total of 752 prepubertal urine samples (median 2, range: 1–6) for creation of individual pools. The median length of follow-up was 10.0 years; 79% of boys were followed beyond age 15. We identified three pubertal progression groups: slower (34%), moderate (43%), and faster (23%) progression. A standard deviation increase in urinary log-monobenzyl phthalate (MBzP) concentrations was associated with higher adjusted odds of being in the slow versus faster pubertal progression trajectory (aOR 1.47, 95% CI 1.06–2.04). None of the other phthalate metabolites were associated with pubertal progression. ConclusionsOn average, boys with higher concentrations of prepubertal urinary MBzP had a slower tempo of pubertal progression, perhaps attributable to the disruption of androgen-dependent biological pathways.

Oxidatively generated DNA damage mediates the associations of exposure to phthalates with uterine fibroids and endometriosis: Findings from TREE cohort

BackgroundEpidemiological studies on phthalate exposures in associations with uterine fibroids (UF) and endometriosis (EMT) are inconsistent. The underlying mechanisms are poorly understood. ObjectivesTo investigate the relationships of urinary phthalate metabolites with UF and EMT risks, and further to examine the mediating role of oxidative stress. MethodsThis study included 83 and 47 women separately diagnosed with UF and EMT, as well as 226 controls from the Tongji Reproductive and Environmental (TREE) cohort. Two spot urine samples from each woman were analyzed for two oxidative stress indicators and eight urinary phthalate metabolites. Unconditional logistic regression models or multivariate regression models were fitted to evaluate the associations among phthalate exposures, oxidative stress indicators, and the risks of UF and EMT. The potential mediating role of oxidative stress was estimated by the mediation analyses. ResultsWe observed that each ln-unit increase in urinary mono-benzyl phthalate (MBzP) concentrations was associated with increased UF risk [adjusted OR (aOR): 1.56, 95% CI: 1.20, 2.02], and that each ln-unit increase in urinary MBzP (aOR: 1.48, 95% CI: 1.09, 1.99), mono-isobutyl phthalate (MiBP) (aOR: 1.83, 95% CI: 1.19, 2.82), and mono-2-ethylhexyl phthalate (MEHP) (aOR: 1.66, 95% CI: 1.19, 2.31) concentrations were associated with increased EMT risk (all FDR-adjusted P < 0.05). Moreover, we observed that all tested urinary phthalate metabolites were positively associated with two oxidative stress indicators [4-hydroxy-2-nonenal-mercapturic acid (4-HNE-MA) and 8-hydroxy-2-deoxyguanosine (8-OHdG)], in which 8-OHdG was associated with increased risks of UF and EMT (all FDR-adjusted P < 0.05). The mediation analyses showed that 8-OHdG mediated the positive relationships of MBzP with UF risk, and of MiBP, MBzP, and MEHP with EMT risk, with the estimated intermediary proportion ranging from 32.7% to 48.1%. ConclusionsOxidatively generated DNA damage may mediate the positive associations of certain phthalate exposures with the risks of UF and EMT. However, further investigation is warranted to confirm these findings.

Exposure to phthalates and DiNCH among preschool children in Sweden: Urinary metabolite concentrations and predictors of exposure

Several plasticizing chemicals induce endocrine disrupting effects in humans, and the indoor environment is suggested to be a source of exposure. As children are particularly vulnerable to the effects from exposure to endocrine disrupting chemicals (EDCs), it is essential to monitor exposure to EDCs such as phthalates and non-phthalate plasticizers in indoor environments intended for use by children. The aim of this study was to assess everyday plasticizer exposure among preschool-aged children in Sweden by measuring urinary plasticizer metabolite concentrations. In addition, it was investigated whether the concentrations would be altered as a result of the children spending part of the day at preschool, in comparison with weekend exposure, when they may spend more time in home environments or engage in various weekend and leisure activities. For this purpose, fourteen metabolites from eight phthalates (di-ethylhexyl phthalate, DEHP; di-n-butyl phthalate, DnBP; di-isobutyl phthalate, DiBP; butyl-benzyl phthalate, BBzP; di-iso-nonyl phthalate, DiNP; di-propylheptyl phthalate, DPHP; di-iso-decyl phthalate, DiDP; and di-ethyl phthalate, DEP) and one non-phthalate plasticizer (di-isononyl cyclohexane 1,2-dicarboxylate, DiNCH) were measured in 206 urine samples collected at four occasions, i.e. twice during the winter and twice during the spring from 54 children (mean5.1 years, SD 0.94) enrolled at eight preschools in Sweden. A detection frequency (DF) of 99.9% for the 14 metabolites indicates a widespread exposure to plasticizers among children in Sweden. Compared to previous Swedish and international studies performed during approximately the same time period, high urinary concentrations of monobenzyl phthalate (MBzP), a metabolite from the strictly regulated BBzP, were measured in this study (median 17ng/mL). Overall, high urinary phthalate metabolite concentrations were observed in this study compared to the US CDC-NHANES from the same time period and similar age-group. Compared to European studies, however, similar concentrations were observed for most metabolites and the urinary concentrations from few participating children exceeded the human biomonitoring guidance values (HBM-GV) for children. After days with preschool attendance, lower urinary concentrations of metabolites originating from DEP and phthalates that are strictly regulated within the EU REACH legislation (DEHP, DnBP, and DiBP) and higher concentrations of metabolites originating from DiNP, DPHP, and DiDP, i.e. less or non-regulated phthalates were found compared the urinary concentrations of these metabolites in weekends. This may indicate that factors in the indoor environment itself are important for the extent of the plasticizer exposure. All the analyzed metabolites were measured in lower concentrations in urine collected from children attending preschools built or renovated after the year 2000, while no seasonal differences were observed in this study.

Urinary Phthalate Metabolites and Slow Walking Speed in the Korean Elderly Environmental Panel II Study.

Previous epidemiological studies have suggested that phthalate exposure may contribute to neurocognitive and neurobehavioral disorders and decreased muscle strength and bone mass, all of which may be associated with reduced physical performance. Walking speed is a reliable assessment tool for measuring physical performance in adults age 60 y and older. We investigated associations between urinary phthalate metabolites and slowness of walking speed in community-dwelling adults ages 60-98 y. We analyzed 1,190 older adults [range, 60-98 y of age; , ] from the Korean Elderly Environmental Panel II study and measured repeatedly up to three times between 2012 and 2014. Phthalate exposure was estimated using the following phthalate metabolites in urine samples: mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-n-butyl phthalate (MnBP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono-benzyl phthalate (MBzP). Slowness was defined as a walking speed of . We used logistic and linear regression models to evaluate the association between each urinary phthalate metabolite and slowness or walking-speed change. We also used Bayesian kernel machine regression (BKMR) to examine overall mixture effects on walking speed. At enrollment, MBzP levels were associated with an increased odds of slowness [odds ratio (OR) per doubling increase: 1.15, 95% confidence interval (CI): 1.02, 1.30; OR for the highest vs. lowest quartile: 2.20 (95% CI: 1.12, 4.35) with p-trend across ]. In longitudinal analyses, MEHHP levels showed an increased risk of slowness [OR per doubling increase: 1.15 (95% CI: 1.02, 1.29), OR for the highest vs. lowest quartile: 1.47 (95% CI: 1.04, 2.06), ]; whereas those with higher MnBP showed a reduced risk of slowness [OR per doubling increase: 0.84 (95% CI: 0.74, 0.96), OR in the highest (vs. lowest) quartile: 0.64 (95% CI: 0.47, 0.87), ]. For linear regression models, MBzP quartiles were associated with slower walking speed () at enrollment, whereas MEHHP quartiles were associated with slower walking speed, and MnBP quartiles were associated with faster walking speed in longitudinal analysis ( and , respectively). Further, the BKMR analysis revealed negative overall trends between the phthalate metabolite mixtures and walking speed and DEHP group (MEHHP, MEOHP, and MECPP) had the main effect of the overall mixture. Urinary concentrations of prevalent phthalates exhibited significant associations with slow walking speed in adults ages 60-98 y. https://doi.org/10.1289/EHP10549.

Associations of urinary metabolite concentrations of phthalates and phthalate replacements with body composition from mid-childhood to early adolescence

BackgroundPhthalates may adversely influence body composition by lowering anabolic hormones and activating peroxisome-proliferator activated receptor gamma. However, data are limited in adolescence when body mass distributions rapidly change and bone accrual peaks. Also, potential health effects of certain phthalate/replacements [e.g., di-2-ethylhexyl terephthalate (DEHTP)] have not been well studied. MethodsAmong 579 children in the Project Viva cohort, we used linear regression to evaluate associations of urinary concentrations of 19 phthalate/replacement metabolites from mid-childhood (median: 7.6 years; 2007–2010) with annualized change in areal bone mineral density (aBMD) and lean, total fat, and truncal fat mass as measured by dual-energy X-ray absorptiometry between mid-childhood and early adolescence (median: 12.8 years). We used quantile g-computation to assess associations of the overall chemical mixture with body composition. We adjusted for sociodemographics and tested for sex-specific associations. ResultsUrinary concentrations were highest for mono-2-ethyl-5-carboxypentyl phthalate [median (IQR): 46.7 (69.1) ng/mL]. We detected metabolites of most replacement phthalates in a relatively small number of participants [e.g., 28% for mono-2-ethyl-5-hydrohexyl terephthalate (MEHHTP; metabolite of DEHTP)]. Detectable (vs. non-detectable) MEHHTP was associated with less bone and greater fat accrual in males and greater bone and lean mass accrual in females [e.g., change in aBMD Z-score/year (95% CI): −0.049 (−0.085, −0.013) in males versus 0.042 (0.007, 0.076) in females; pinteraction<0.01]. Children with higher concentrations of mono-oxo-isononyl phthalate and mono-3-carboxypropyl phthalate (MCPP) had greater bone accrual. Males with higher concentrations of MCPP and mono-carboxynonyl phthalate had greater accrual of lean mass. Other phthalate/replacement biomarkers, and their mixtures, were not associated with longitudinal changes in body composition. ConclusionsConcentrations of select phthalate/replacement metabolites in mid-childhood were associated with changes in body composition through early adolescence. As use of phthalate replacements such as DEHTP may be increasing, further investigation can help better understand the potential effects of early-life exposures.

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.

Prenatal and current phthalate exposure and cognitive development in 7-year-old children from the Odense child cohort

BackgroundPhthalates are endocrine disrupters used in a variety of consumer products. Human studies suggest an association between phthalate exposure and cognitive development but adverse effects of the recently introduced phthalate substitutes have only been sparsely studied. ObjectivesTo investigate associations between prenatal and concurrent exposure to phthalates and IQ in 7-year-old children from the Odense Child Cohort. MethodsPregnant women from the Odense Child Cohort had phthalate metabolites measured in urine samples during 3rd trimester in 2010 to 2012. In addition, phthalates were also measured in urine samples from their offspring at age 7 years. IQ was assessed at age 7 years using four subtests from Wechsler Intelligence Scale for Children. The total study population consisted of 585 mother-child pairs with available prenatal urinary phthalate metabolites concentrations and IQ data at age 7 years. A subset of those (N = 274) had urinary phthalate metabolites measured in child urine at age 7 years. Phthalate concentrations were grouped into tertiles and associations with IQ were investigated using multiple linear regression adjusting for sex, maternal education and maternal/child BMI. ResultsUrinary phthalate metabolite concentrations both in pregnant women and children were generally lower compared to previous cohorts. Children with high prenatal urinary concentrations of MEP and metabolites of DEHP (∑DEHPm)(3rd tertile) had −3.1 (95% CI: −5.5, −0.6) (MEP) and − 3.0 (−5.5, −0.6) (∑DEHPm) IQ points at age 7 years compared to children with low concentrations (1st tertile). High concurrent urinary phthalate concentrations of MCPP, ∑DnHxPm, ∑DiDPm and ∑DiNPm in the 3rd tertile was associated with −3.7 (−7.2, −0.2), −4.4 (−7.9, −0.9), −3.7 (−7.2, −0.2) and − 5.6 (−9.1, −2.2) IQ points, respectively, compared to those with the lowest concentrations (1st tertile). ConclusionWe found significant inverse associations between some prenatal and concurrent urinary phthalate concentrations and IQ at age 7 years in this low exposed population. This suggests that exposure to phthalates both prenatally and during early childhood could be hazardous to child neurodevelopment, however, large-scale prospective studies assessing phthalate exposure through multiple urine samples, and possibly investigating cocktail effects of the chemicals as well as long term follow-up are warranted.

Predictors of urinary biomarker concentrations of phthalates and some of their replacements in children in the Project Viva cohort.

Some phthalates are still widely used in food packaging, toys, and personal care products, and links to adverse health have motivated substitution with replacement chemicals. Few studies have examined patterns and predictors of phthalate replacement biomarkers in children. To examine associations of sociodemographic, dietary, and urine collection characteristics with urinary concentrations of biomarkers of select phthalates and their replacements in mid-childhood. We studied 830 children ages 6-10 years in 2007-2010 in a Boston-area cohort. We quantified urinary metabolites and summed their concentrations to calculate biomarkers of the concentrations of ten parent phthalates/replacements. We used linear regression to examine mutually adjusted associations of each predictor with each phthalate biomarker. We used logistic regression to examine predictors of 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) biomarker detectability. Predictor characteristics explained 25-48% of urinary biomarker variability. Di-2-ethylhexyl terephthalate (DEHTP) biomarker was higher in females (18.7% [95% CI: 0.7, 39.9]), children who consumed more meat and dairy, and samples collected from later years. DINCH biomarker was more detectable in females (odds ratio [OR] 2.1 [95% CI: 1.5, 3.0]) and samples from later years. Populations of children with increased urinary concentrations of phthalate and replacement biomarkers can be targeted for future study of sources of exposure, and identifying dietary predictors of biomarkers will directly guide future interventions. Our study uses data from a large cohort that is one of the first to measure DINCH, DEHTP, and metabolites of di-isononyl phthalate and di-isodecyl phthalate. Additionally, we evaluate predictors during mid-childhood when biomarkers might be highest. As the use of replacement phthalates increases, our study is one of the first to examine biomarker patterns and predictors among children.