Mono-isobutyl Phthalate Research Articles

Breast cancer is associated with methylation and expression of the a disintegrin and metalloproteinase domain33 (ADAM33) gene affected by endocrine‑disrupting chemicals.

A disintegrin and metalloproteinase domain33 (ADAM33) gene is a transmembrane glycoprotein that mediates changes in cell adhesion and plays an important role in cancer progression. Since bisphenolA (BPA) and phthalates are epigenetically toxic, the purpose of this study was to examine whether BPA and phthalate metabolites, including monoethyl phthalate(MEP), mono‑n‑butyl phthalate (MBP), mono‑isobutyl phthalate(MIBP), mono(2‑ethylhexyl) phthalate(MEHP), mono(2‑ethyl‑5‑hydroxyhexyl) phthalate (MEHHP), mono(2‑ethyl‑5‑carboxypentyl) phthalate (MECPP), and mono(2‑ethyl‑5‑oxohexyl) phthalate (MEOHP), have an epigenetic impact on ADAM33 and the incidence of breast cancer. CpG islands of breast cancer microarraydatasets obtained from the Gene Expression Omnibus (GEO) were used to assess the ADAM33 methylation profile. We designed a case‑control study including 44cases and 22age‑matched controls to detect the methylation status of intron1 in ADAM33 from peripheral blood mononuclear cells (PBMCs) in blood, using BSP, nested PCR, and bisulfite sequencing, and measured the in vivo gene expression of ADAM33 and the urinary concentrations of endocrine‑disrupting chemicals(EDCs), using real‑time PCR, high‑performance liquid chromatography(HPLC) and liquid chromatography-mass spectrometry(LC‑MS). Only one dataset, GSE32393, reached significance(P=0.016). ADAM33 expression and methylation frequencies at CpG site3 in intron1 were higher in the control group. We found a positive association between intron1 methylation level and ADAM33 expression as well as urinary concentrations of MEHHP, MECPP, MEOHP and Σ4MEHP (the sum of MEHP, MECPP, MEHHP, and MEOHP) in the cases. This study suggests that metabolites of phthalate such as MEHHP, MECPP, MEOHP and Σ4MEHP may increase the intron1 methylation level to elevate ADAM33 gene expression and have a protective effect on reducing the risk of breast cancer.

Increased risk of phthalates exposure for recurrent pregnancy loss in reproductive-aged women

Recurrent pregnancy loss (RPL) is the termination of pregnancies, usually before 20 weeks of gestation, and is defined as the loss of two or more pregnancies. In Taiwan, after 2011 di-2-ethylhexyl phthalate (DEHP) exposure episode, more reproductive-aged women still expose to high levels of DEHP and di-butyl phthalate (DBP) than have women of other age groups. Phthalates might be involved in the RPL pathogenesis. This study assessed the association of phthalate exposure with RPL risk in reproductive-aged Taiwanese women.This study recruited 103 patients diagnosed by a physician with RPL of unknown etiology and 76 controls from the Department of Obstetrics and Gynecology at a medical center in southern Taiwan between August 2013 and August 2017. Urine samples were analyzed for 11 phthalate metabolites through liquid chromatography–tandem mass spectrometry; subsequently, principal component analysis (PCA) and hierarchical clustering analysis were performed to determine the main sources of phthalate exposure. Finally, multivariate logistic regression was used to determine the RPL risk.The creatinine-unadjusted median levels of mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) in RPL/control were 9.8/5.3, 27.2/13.1, 11.4/8.1, and 12.9/9.5 ng/mL, respectively; furthermore, ΣDBPm and ΣDEHPm in RPL/control were 0.18/0.10 and 0.15/0.12 nmol/mL, respectively. PCA revealed three primary components of phthalate exposure: diethyl phthalates (DEP), DEHP, and DBP. Plastic food container use and medication were identified as the main phthalate exposure sources. After adjustment for potential confounding factors (urinary creatinine, age, age at menarche, education, and plastic food container use), we found that the urinary level of ΣDBPm was significantly associated with elevated risk for RPL (OR = 2.85, p = 0.045).Our findings supported the hypothesis that exposure to phthalates increases RPL risk. The development of a strategy to reduce phthalate exposure among reproductive-aged women should be emphasized.

Trimester-specific phthalate concentrations and glucose levels among women from a fertility clinic

BackgroundSubfertile women are at increased risk of glucose intolerance in pregnancy. Based on epidemiologic studies, exposure to certain phthalates is associated with diabetes, elevated glucose, and increased insulin resistance.ObjectivesTo evaluate the association between urinary phthalate metabolites and pregnancy glucose levels in women seeking medically assisted reproduction.MethodsWe evaluated 245 women participating in a prospective cohort study based at a large fertility clinic who delivered live births and had data on pregnancy urinary phthalate metabolite concentrations and blood glucose levels. Urinary phthalate metabolite concentrations were from single spot urine samples collected in 1st and 2nd trimesters. Blood glucose data was abstracted from medical records for non-fasting 50-g glucose challenge tests at 24–28 weeks gestation. Multivariable linear regression models were used to evaluate associations between 7 urinary phthalate metabolites in quartiles and mean glucose adjusted for potential confounders.ResultsEighteen percent of women had glucose levels ≥ 140 mg/dL. Second trimester monoethyl phthalate (MEP) concentrations were positively associated with glucose levels, with adjusted mean (95%CI) glucose levels of 121 mg/dl (114, 128) vs. 109 mg/dL (103, 116) for women in highest and lowest quartiles, respectively. Women in the highest quartile of second trimester mono-isobutyl phthalate (MiBP) concentrations had a mean glucose level 14 mg/dL lower compared to women in the lowest quartile. No other urinary phthalate metabolites were associated with glucose levels.ConclusionsMEP and MiBP—metabolites of diethyl phthalate and dibutyl phthalate, respectively—were associated with higher pregnancy glucose in subfertile women—a population at high risk of glucose intolerance in pregnancy.

Austrian reference values for phthalate metabolite exposure in children/adolescents and adults

Reference values (RV95) are statistically derived values comprising the rounded 95th percentiles within the 95% confidence interval and indicate the upper margin of background exposure to chemical substances in a population at a given time period. Based on representative national human biomonitoring data on several urinary phthalate metabolites in children, adolescents and adults from 2010 to 2011, RV95 were derived for the Austrian population based on a IUPAC guideline and the recommendation of the German Human Biomonitoring Commission. The RV95 (rounded values) for phthalate metabolites in children and adolescents aged 6-15 years are 110 μg/l (confidence interval of 95th population percentile: 83.7-163) for mono-ethyl phthalate (MEP), 45 μg/l (40.9-60.6) for mono-n-butyl phthalate (MnBP), 130 μg/l (126-161) for mono-isobutyl phthalate (MiBP), 25 μg/l (17.8-33.6) for mono-benzyl phthalate (MBzP), 100 μg/l (94.0-126) for the sum of the di(2-ethylhexyl) phthalate (DEHP) metabolites including mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP) and mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP), and 1.5 μg/l (0.64-1.6) for mono-cyclohexyl phthalate (MCHP). In adults aged 18-81 years, RV95 are 440 μg/l (353-636) for MEP, 40 μg/l (33.1-52.1) for MnBP, 110 μg/l (87.3-118) for MiBP, 10 μg/l (7.2-11.8) for MBzP, 50 μg/l (44.6-68.3) for the sum of MEHP, 5OH-MEHP, 5oxo-MEHP and 5cx-MEPP, and 1.5 μg/l (0.95-1.8) for MCHP. For almost all investigated metabolites, children and adolescents exhibit higher RV95 than adults, with the exceptions being MEP and MCHP. Compared to available RV95 for Germany and Canada, Austrian values are lower for all investigated population groups.

Exposure to Bisphenol A and phthalates metabolites in the third trimester of pregnancy and BMI trajectories.

Bisphenol A (BPA) and phthalates metabolites are linked to a variety of adverse health consequences but studies have not explored their association with growth trajectories. Explore body mass index (BMI) trajectories for tertile exposures to BPA and phthalates metabolites in the third trimester of pregnancy. We constructed BMI (kg/m2 ) trajectories from birth to 14years in a birth cohort of 249 children from Mexico City using tertiles of third trimester maternal urinary concentrations of BPA and phthalates metabolites. Fractional age polynomials and mixed effects models were fit separately by sex. Predicted models were plotted for each metabolite tertile with the covariates mother's education and BMI centered at average values. Highest predicted BMI trajectories for female children were observed for third tertile exposure to the phthalate metabolite mono(2-ethyl-5-carboxypentyl) phthalate. In male children, first tertile exposure to mono-isobutyl phthalate and monobenzyl phthalate and second tertile exposure to mono(2-ethylhexyl) phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate predicted the highest BMI trajectory by adolescence. There was no relationshsip between BPA and child growth trajectory. These results suggest sex-specific differences in BMI trajectories by levels of metabolite exposure. Additional studies are needed to consider growth through adolescence in assessing the association of pregnancy exposures on child's BMI.

Maternal urinary phthalate metabolites during pregnancy and thyroid hormone concentrations in maternal and cord sera: The HOME Study.

Phthalates, endocrine-disrupting chemicals that are commonly found in consumer products, may adversely affect thyroid hormones, but findings from prior epidemiologic studies are inconsistent. In a prospective cohort study, we investigated whether maternal urinary phthalate metabolite concentrations and phthalate mixtures measured during pregnancy were associated with thyroid hormones among pregnant women and newborns. We measured nine phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate, mono-isobutyl phthalate, monobenzyl phthalate (MBzP), and four monoesthers of di(2-ethylhexyl) phthalate] in urine collected at approximately 16 and 26 weeks' gestation among women in the Health Outcomes and Measures of the Environment Study (2003-2006, Cincinnati, Ohio). Thyroid stimulating hormone (TSH) and free and total thyroxine and triiodothyronine were measured in maternal serum at 16 weeks' gestation (n = 202) and cord serum at delivery (n = 276). We used multivariable linear regression to assess associations between individual urinary phthalate metabolites and concentrations of maternal or cord serum thyroid hormones. We used weighted quantile sum regression (WQS) to create a phthalate index describing combined concentrations of phthalate metabolites and to investigate associations of the phthalate index with individual thyroid hormones. With each 10-fold increase in 16-week maternal urinary MEP, maternal serum total thyroxine (TT4) decreased by 0.52 μg/dL (95% CI: -1.01, -0.03). For each 10-fold increase in average (16- and 26-week) maternal urinary MBzP, cord serum TSH decreased by 19% (95% CI: -33.1, -1.9). Among mothers, the phthalate index was inversely associated with maternal serum TT4 (WQS beta = -0.60; 95% CI: -1.01, -0.18). Among newborns, the phthalate index was inversely associated with both cord serum TSH (WQS beta = -0.11; 95% CI: -0.20, -0.03) and TT4 (WQS beta = -0.53; 95% CI: -0.90, -0.16). Our results suggest that co-exposure to multiple phthalates was inversely associated with certain thyroid hormones (TT4 in pregnant women and newborns, and TSH in newborns) in this birth cohort. These findings highlight the need to study chemical mixtures in environmental epidemiology.

Phthalate metabolite exposures among immigrants living in the United States: findings from NHANES, 1999–2014

Phthalates exposure has been linked to multiple health risks, and US immigrants may have different exposures to phthalates due to lifestyle differences. Urinary concentrations of eight phthalate metabolites (mono-ethyl phthalate [MEP], mono-n-butyl phthalate [MnBP], mono-isobutyl phthalate [MiBP], mono-(3-carboxypropyl) phthalate [MCPP], mono-benzyl phthalate [MBzP], mono-2-ethylhexyl phthalate [MEHP], mono-(2-ethyl-5-hydroxyhexyl) phthalate [MEHHP], mono-(2-ethyl-5-oxohexyl) phthalate [MEOHP]) were measured in 10318 US-born and 3511 foreign-born individuals from NHANES 1999-2014. Using multivariate adjusted linear regression, we assessed whether phthalate metabolite levels differed by nativity in the whole population, within racial/ethnic groups, and by years in the US. We also tested whether immigrant demographics predicted phthalate metabolite levels. In fully adjusted models, MEP, MnBP, and MiBP were significantly higher, and MBzP significantly lower, among immigrants than US-born participants. Among immigrants, MnBP and MiBP significantly declined with longer time in the US (Ptrend = 0.029 and Ptrend =0.039, respectively), while MCPP and MBzP significantly rose (Ptrend = 0.019 and Ptrend =0.043, respectively). Results within each racial/ethnic group were consistent with the whole population. Among immigrants, women had significantly higher metabolite levels than men (all p<0.01), and MEP, MnBP, and MCPP differed by race/ethnicity. Due to higher phthalate exposures, immigrants may be especially vulnerable to phthalate-associated health problems.

Simultaneous determination of primary and secondary phthalate monoesters in the Taihu Lake: Exploration of sources

While phthalates monoesters have been recognized as the bioactive metabolites of phthalates, the knowledge on their environmental occurrence and sources is limited. In this study, monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and mono-2-ethylhexyl phthalate (MEHP) were frequently detected in water samples from the Taihu Lake in China using an improved SPE-LC-MS-MS method. The mean concentrations for MMP, MEP, MiBP, MnBP, and MEHP were 51.7 ± 25.2, 6.0 ± 4.8, 19.6 ± 14.6, 42.2 ± 64.7, and 33.0 ± 37.4 ng/L, respectively, while those of their corresponding parent chemicals, DMP, DEP, DiBP, and DnBP and DEHP, were 36.54 ± 43.22, 42.64 ± 66.66, 246.8 ± 311.1, 524.7 ± 586.9, and 208.1 ± 223.5 ng/L, respectively. Three secondary monoesters of DEHP, mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) were for the first time detected with mean concentration of 1.27 ± 1.33, 1.33 ± 1.54, and 0.73 ± 0.79 ng/L, respectively. The percentage of the sum concentration of MEOHP, MEHHP, and MECPP relative to total concentration of DEHP metabolites was 5.3–12.4%. DEHP was identified to be biodegraded into secondary phthalate monoesters in water from the Taihu Lake, but their contribution to the total concentration of DEHP metabolites was 1.2–3.6%, lower than those in the Taihu Lake. Primary and secondary DEHP monoesters were also detected in influents and effluents of two sewage treatment plants adjacent to the Taihu Lake, the percentages of secondary DEHP monoesters in influents were 5.8% and 11.3%, similar with those in the Taihu Lake. Taken together with their relatively high concentrations in influents, the discharging of domestic wastewater may be an important contributor to the occurrence of phthalate monoesters in the Taihu Lake.

A cross sectional study of urinary phthalates, phenols and perchlorate on thyroid hormones in US adults using structural equation models (NHANES 2007–2008)

BackgroundBiomonitoring data shows that people are exposed to phthalates, phenols and perchlorates. Many of these compounds are endocrine disrupting compounds that affect thyroid hormone levels. Yet the effect of these compounds on thyroid hormone levels are often evaluated individually rather than as a mixture. Our objective was to examine the association between 11 urinary endocrine disrupting compounds and thyroid hormones using structural equation models. MethodsUsing data from the National Health and Nutrition and Examination Survey 2007–2008, we fit a latent variable utilizing urinary measurements of 9 compounds in females (perchlorate, bisphenol A, benzophenone-3, mono-2ethyl5carboxypentyl phthalate, mono-n-butyl phthalate, mono-(3-carboxypropyl) phthalate, mono(2ethyl5hydroxyhexyl) phthalate, mono-benzyl phthalate, and mono-isobutyl phthalate) and 8 compounds in males (without benzophenone-3). The association of the latent variable with serum thyroid hormones (Total T3, Total T4, and Thyroid Stimulating Hormones) was assessed in females (N = 710) and males (N = 850) over the age of 12 controlling for age, race, and urinary creatinine. ResultsIn males, urinary endocrine disrupting compound levels were negatively associated with thyroxine (β: −0.19, 95% Confidence Interval (95% CI): −0.31, −0.05). In females, urinary endocrine disrupting compound levels were positively associated with triiodothyronine serum concentrations (β: 0.09, 95% CI: −0.03, 0.21) however this association was not statistically significant. ConclusionsThis cross-sectional analysis provides additional evidence that environmental exposure to phthalates and phenols is associated with endocrine-related processes. Furthermore, these results suggested sex-specific differences in exposure to endocrine disrupting mixtures, and the exposure-response between endocrine disrupting mixtures and thyroid hormone levels. Specifically, higher exposure to a mixture of endocrine disrupting compounds was associated with lower levels of total T4 in males but not in females. While a structural methodological framework was used to assess these complex relationships, the cross sectional nature of this analysis limits causal inference and further research is needed to determine the clinical significance of these findings.

Association of phthalate exposures with urinary free cortisol and 8-hydroxy-2′-deoxyguanosine in early childhood

Several studies suggested potential links of phthalates to stress-related outcomes. However, limited evidence has been available for the relationships between phthalate metabolites and free cortisol and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in perinatal and postnatal environments. Therefore, we evaluated the relationships between phthalate metabolites and free cortisol and 8-OHdG in mother–child pairs. We repeatedly collected urine samples of 287 mother–child pairs from just before delivery to 15 months of age to measure the levels of four phthalate metabolites – mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-isobutyl phthalate (MiBP), and mono-n-butyl phthalate (MnBP) – and free cortisol and 8-OHdG. We used linear mixed effect models and generalized additive mixed models to estimate the relationship between the phthalate metabolites and free cortisol and 8-OHdG after adjusting for the child's gender, urine collection time, and maternal smoking status. The four phthalate metabolite levels were strongly correlated each other (all, p < .0001), and intra-class correlation for each metabolite in children ranged from 0.18 to 0.96. All four phthalate metabolites were positively associated with both free cortisol (MEHHP, β = 0.18 and p < .0001; MEOHP, β = 0.17 and p < .0001; MiBP, β = 0.13 and p = .0001; MnBP, β = 0.21 and p < .0001; and molar sum of metabolites, β = 0.21 and p < .0001) and 8-OHdG (MEHHP, β = 0.20 and p < .0001; MEOHP, β = 0.18 and p < .0001; MiBP, β = 0.23 and p < .0001; MnBP, β = 0.28 and p < .0001; and molar sum of metabolites, β = 0.29 and p < .0001) in childhood. Our findings suggest that phthalate exposures increase free cortisol and 8-OHdG levels in early childhood.

Placental lncRNA Expression Is Associated With Prenatal Phthalate Exposure.

Phthalates are endocrine-disrupting chemicals that can cross the placenta and affect the fetal epigenome. Among various epigenetic regulators of gene expression, long noncoding RNAs (lncRNAs) are important players that may also be involved in the manifestation of endocrine-disrupting chemical toxicity. We sought to explore the association between maternal urinary phthalate metabolite concentrations and lncRNA expression in human placenta to better understand potential mechanisms through which lncRNAs participate in mediating phthalate toxicity. Ten patients with uncomplicated dichorionic diamniotic twin pregnancies at term were included in this study. Urinary (n = 10) and placenta samples (n = 20) were collected for all participants. Urinary samples were analyzed for 15 phthalate metabolites and 2 phthalate alternative metabolites. Real-time PCR arrays were used to identify and quantify 87 lncRNAs from the placental samples. We tested the Spearman correlation matrix to compare prenatal phthalate measures against placental lncRNA levels. lncRNA levels showed large variations across samples, with no significant differences in lncRNA expression within twin pairs. Mono-(carboxynonyl) phthalate demonstrated consistently strong correlations with most lncRNAs. The strongest correlation was observed between mono-hydroxyisobutyl phthalate and LOC91450 (Rspearman = 0.88, p < .001). This correlation remained significant after Bonferroni adjustment. Other strong correlations were observed between mono-isobutyl phthalate, DPP10 and HOTTIP (Rspearman = -0.91, p < .001). AIRN, DACT3.AS1, DLX6, DPP10, HOTTIP, LOC143666, and LOC91450 were strongly correlated with the greatest number of phthalate metabolites. Further studies are needed to validate these results and understand if the altered expression of lncRNAs in human placenta has clinical significance.

Association between prenatal bisphenol A and phthalate exposures and fetal metabolic related biomarkers: The Hokkaido study on Environment and Children's Health

Bisphenol A and phthalates are widely detected in human urine, blood, breast milk, and amniotic fluid. Both bisphenol A and phthalates have been suggested as playing a role in obesity epidemics. Exposure to these chemicals during fetal development, and its consequences should be concerning because they can cross the placenta. Thus, this study aimed to assess the association between prenatal exposure to bisphenol A and phthalates, and cord blood metabolic-related biomarkers. Maternal serum was used during the first trimester, to determine prenatal exposure to bisphenol A and phthalates. Levels of metabolic-related biomarkers in the cord blood were also determined. Linear regression models were applied to the 365 participants with both, exposure and biomarker assessments, adjusted for maternal age, pre-pregnancy body mass index, parity, education, and sex of the child. The level of bisphenol A was negatively associated with the leptin level (β = −0.06, 95% confidence interval [CI]: −0.11, −0.01), but was positively associated with the high-molecular-weight adiponectin level, with marginal significance (β = 0.03, 95%CI: 0.00, 0.06). The mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-(2-ethylhexyl) phthalate (MEHP), and summation of MEHP and MECPP to represent DEHP exposure (∑DEHPm) levels were inversely associated with the leptin levels (β=−0.14, 95%CI: −0.27, −0.01; β = −0.12, 95%CI: −0.24, 0.00 with marginal significance; β=0.08, 95%CI: −0.14, −0.03; and β = −0.09, 95%CI: −0.16, −0.03, respectively). The present study provided some evidence that prenatal exposure to bisphenol A and certain phthalates may modify fetal adiponectin and leptin levels.

Longitudinal assessment of prenatal phthalate exposure on serum and cord thyroid hormones homeostasis during pregnancy - Tainan birth cohort study (TBCS)

An increasing number of studies have revealed that phthalate exposure alters thyroid hormone homeostasis in the general population, but there is insufficient evidence of the effect of longitudinal maternal phthalate exposure on maternal and fetal thyroid hormones during pregnancy. We longitudinally assessed the effect of prenatal phthalate exposure in pregnant women on umbilical cord and maternal thyroid hormones at three trimesters during pregnancy. We recruited 98 pregnant women and collected urine and blood samples at three trimesters in an obstetrics clinic in Southern Taiwan from 2013 to 2014. We analyzed the concentrations of 11 urinary phthalate metabolites, including monoethylhexyl phthalate, mono-(2-ethyl-5-oxo-hexyl) phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-n-butyl phthalate, monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), using online liquid chromatography–tandem mass spectrometry. The cord and maternal serum levels of thyroxine (T4), free T4, triiodothyronine (T3), thyroid-stimulating hormone (TSH), and thyroxine-binding globulin were measured using an electrochemiluminescence immunoassay. A mixed-model analysis was utilized to assess the effect of longitudinal phthalate exposure on thyroid hormones and adjusted for significant covariates. We found that urinary MiBP (β=−0.065, 95% confidence interval (CI): −0.124, −0.005), and MEOHP (β=−0.083, 95% CI: −0.157, −0.009) were significantly negatively associated with serum TSH. Urinary MECPP was inversely related to serum T3 (β=−0.027, 95% CI: −0.047, −0.006). Urinary MEP (β=0.014, 95% CI: −0.001, 0.028) and MiBP (β=0.033, 95% CI: 0.018, 0.049) were positively related to free T4. We found that cord serum T3 (β=0.067, 95% CI: 0.003, 0.131) and free T4 (β=0.031, 95% CI: 0.001, 0.062) levels had significant positive associations with maternal ΣDBPm levels at the second trimester. We concluded that different phthalates exposure windows during gestation may alter cord and serum thyroid hormone homoeostasis.

Prevalence and predictors of phthalate exposure in pregnant women in Charleston, SC

Phthalates are plasticizers commonly detected in human urine due to widespread exposure from PVC plastics, food packaging, and personal care products. Several phthalates are known antiandrogenic endocrine disruptors, which raises concern for prenatal exposure during critical windows of fetal development. While phthalate exposure is ubiquitous, certain demographics are subject to greater or lesser exposure. We sampled urine from 378 pregnant women during the second trimester of gestation living in Charleston, SC, and measured eight urinary phthalate metabolites as biomarkers of phthalate exposure: monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), and monomethyl phthalate (MMP). Demographic data was collected from questionnaires administered at the time of specimen collection. All phthalate metabolites were detected in over 93% of urine samples. On average, concentrations were highest for MEP (median = 47.0 ng/mL) and lowest for MMP (median = 1.92 ng/mL). Sociodemographic characteristics associated with elevated phthalate concentrations included being unmarried, less educated, having a low income, high body mass index (BMI), and/or being African American. After racial stratification, age, BMI, education, and income were significantly associated with phthalate concentrations in African American women. Marital status was associated with phthalate concentrations in Caucasian women only, with greater concentrations of MBP, MEHHP, MiBP, and MMP in unmarried versus married women. Results of this cross-sectional study provide evidence for significant racial and demographic variations in phthalate exposure.

Associations between Birthweight, Mono-isobutyl Phthalate Concentrations, Behaviors, Non-chemical Stressors and Overweight and Obesity in Young U.S. Adolescents

Associations between Birthweight, Mono-isobutyl Phthalate Concentrations, Behaviors, Non-chemical Stressors and Overweight and Obesity in Young U.S. Adolescents

Paternal and maternal preconception urinary phthalate metabolite concentrations and child behavior

BackgroundPrenatal phthalate exposure has been associated with behavioral problems and lower performance on measures of cognitive ability in children. However, the potential effect of phthalate exposure during the sensitive preconception period is unknown. ObjectivesTo estimate the association of maternal and paternal preconception urinary phthalate metabolite concentrations with child behavior and evaluate potential modification by child sex. MethodsWe used data from 166 children (111 singletons, 26 pairs of twins, and 1 set of triplets) born to 134 mothers and 100 fathers participating in a prospective preconception cohort study of subfertile couples from the Massachusetts General Hospital Fertility Center. We estimated mean maternal and paternal preconception exposures by averaging individual phthalate metabolite concentrations in multiple urine samples collected before pregnancy. We assessed children's behavior at 2–9 years of age by parent report using the Behavior Assessment System for Children-2 (BASC-2). We estimated the covariate-adjusted association between individual phthalate metabolite concentrations and the sum of di(2-ethylhexyl) phthalate metabolites (∑ DEHP) and behavior scores, and evaluated differences in associations by child sex using linear regression with Generalized Estimating Equations. Models were further adjusted for prenatal phthalate concentrations in sensitivity analyses. ResultsEach loge-unit increase in maternal and paternal preconception concentrations of ∑DEHP was associated with a 2.0 (95% CI: − 3.2, − 0.7) and 1.8 (95% CI: − 3.1, − 0.4) point decrease in BASC-2 internalizing behavior scores among all children, respectively. We observed sex-specific associations for some phthalate biomarkers: among boys, maternal monoisobutyl phthalate (MiBP) was positively associated with externalizing behaviors, and paternal MiBP and mono-n-butyl phthalate were positively associated with internalizing behaviors. ConclusionsIn this cohort, paternal and maternal preconception concentrations of some phthalate biomarkers were associated with specific aspects of child behavior, even after adjustment for prenatal concentrations. While additional research is warranted to confirm these results, our findings suggest that the preconception period of exposure may be a critical window for offspring neurodevelopment.

Dietary exposure to di-isobutyl phthalate increases urinary 5-methyl-2′-deoxycytidine level and affects reproductive function in adult male mice

Phthalates are a large family of ubiquitous environmental pollutants suspected of being endocrine disruptors. Epidemiological studies have associated phthalate metabolites with decreased reproductive parameters and linked phthalate exposure with the level of urinary 5-methyl-2′-deoxycytidine (5mdC, a product of methylated DNA). In this study, adult male mice were exposed to 450mg di-isobutyl phthalate (DiBP)/(kg·day) via dietary exposure for 28days. Mono-isobutyl phthalate (MiBP, the urinary metabolite) and reproductive function parameters were determined. The levels of 5mdC and 5-hydroxymethyl-2′-deoxycytidine (5hmdC) were measured in urine to evaluate if their contents were also altered by DiBP exposure in this animal model. Results showed that DiBP exposure led to a significant increase in the urinary 5mdC level and significant decreases in sperm concentration and motility in the epididymis, accompanied with reduced testosterone levels and down-regulation of the P450 cholesterol side-chain cleavage enzyme (P450scc) gene in the mice testes. Our findings indicated that exposure to DiBP increased the urinary 5mdC levels, which supported our recent epidemiological study about the associations of urinary 5mdC with phthalate exposure in the male human population. In addition, DiBP exposure impaired male reproductive function, possibly by disturbing testosterone levels; P450scc might be a major steroidogenic enzyme targeted by DiBP or other phthalates.

Exposure sources and their relative contributions to urinary phthalate metabolites among children in Taiwan.

Phthalate exposure is omnipresent and known to have developmental and reproductive effects in children. The aim of this study was to determine the phthalate exposure sources and their relative contributions among children in Taiwan. During the first wave of the Risk Assessment of Phthalate Incident in Taiwan (RAPIT), in 2012, we measured 8 urinary phthalate metabolites in 226 children aged 1-11 years old and in 181 children from the same cohort for the wave 2 study in 2014. A two-stage statistical analysis approach was adopted. First, a stepwise regression model was used to screen 80 questions that explored the exposure frequency and lifestyle for potential associations. Second, the remaining questions with positive regression coefficients were grouped into the following 6 exposure categories: plastic container/packaging, food, indoor environment, personal care products, toys, and eating out. A mixed model was then applied to assess the relative contributions of these categories for each metabolite. The use of plastic container or food packaging were dominant exposure sources for mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and mono-n-butyl phthalate (MnBP). The indoor environment was a major exposure source of mono-methyl phthalate (MMP), mono-benzyl phthalate (MBzP), and mono-isobutyl phthalate (MiBP). The consumption of seafood showed a significant correlation with MEHP. The children's modified dietary behavior and improved living environment in the second study wave were associated with lower phthalate metabolite levels, showing that phthalate exposures can be effectively reduced.

Maternal urinary phthalates and sex-specific placental mRNA levels in an urban birth cohort

BackgroundPrenatal urinary concentrations of phthalates in women participants in an urban birth cohort were associated with outcomes in their children related to neurodevelopment, autoimmune disease risk, and fat mass at 3,5,7, and 8 years of life. Placental biomarkers and outcomes at birth may offer biologic insight into these associations. This is the first study to address these associations with candidate genes from the phthalate and placenta literature, accounting for sex differences, and using absolute quantitation methods for mRNA levels.MethodsWe measured candidate mRNAs in 180 placentas sampled at birth (HSD17B1, AHR, CGA, CYP19A1, SLC27A4, PTGS2, PPARG, CYP11A1) by quantitative PCR and an absolute standard curve. We estimated associations of loge mRNA with quartiles of urinary phthalate monoesters using linear mixed models. Phthalate metabolites (N = 358) and mRNAs (N = 180) were transformed to a z-score and modeled as independent, correlated vectors in relation to large for gestational age (LGA) and gestational diabetes mellitus (GDM).ResultsCGA was associated with 4 out of 6 urinary phthalates. CGA was 2.0 loge units lower at the 3rd vs. 1st quartile of mono-n-butyl phthalate (MnBP) (95% confidence interval (CI): −3.5, −0.5) in male placentas, but 0.6 loge units higher (95% CI: −0.8, 1.9) in female placentas (sex interaction p = 0.01). There was an inverse association of MnBP with PPARG in male placentas (−1.1 loge units at highest vs. lowest quartile, 95% CI: −2.0, −0.1). CY19A1, CYP11A1, CGA were associated with one or more of the following in a sex-specific manner: monobenzyl phthalate (MBzP), MnBP, mono-iso-butyl phthalate (MiBP). These 3 mRNAs were lower by 1.4-fold (95% CI: −2.4, -1.0) in male GDM placentas vs. female and non-GDM placentas (p-value for interaction = 0.04). The metabolites MnBP/MiBP were 16% higher (95% CI: 0, 22) in GDM pregnancies.ConclusionsPrenatal concentrations of certain phthalates and outcomes at birth were modestly associated with molecular changes in fetal placental tissue during pregnancy. Associations were stronger in male vs. female placentas, and associations with MnBP and MiBP were stronger than other metabolites. Placental mRNAs are being pursued further as potential mediators of exposure-induced risks to the health of the child.

Toxicoanthropology: Phthalate exposure in relation to market access in a remote forager-horticulturalist population

Phthalates are a class of plasticizing chemicals produced in high volume and widely found in consumer products. Evidence suggests that phthalates may have non-monotonic effects on reproductive hormone activity. With exposure to phthalates virtually ubiquitous among industrialized populations, identifying unexposed and/or minimally exposed human populations is essential for understanding the effects of low level exposures. Our primary objective was to quantify urinary phthalate metabolite concentrations in the Tsimane', a remote population of Bolivian forager-horticulturalists. Our secondary objectives were to determine if phthalate metabolite concentrations vary in relation to access to market goods; and to explore relationships between phthalate and reproductive hormone metabolite concentrations. Given that phthalate exposure is of particular concern during fetal development, we focused on reproductive age women in the current analyses. Phthalate metabolites were assayed in urine samples from 59 naturally cycling, reproductive age Tsimane' women. Market access was assessed as: (1) distance from residence to the largest nearby town (San Borja, Bolivia) and (2) Spanish fluency. Urinary reproductive hormone metabolite concentrations were quantified using enzyme immunoassays. We fit linear models to examine: (1) predictors of phthalate exposure; and (2) relationships between urinary phthalate and reproductive hormone metabolite concentrations. Eight phthalate metabolites were detectable in at least 75% of samples. Median concentrations were up to an order of magnitude lower than industrialized populations. Proximity to San Borja and Spanish fluency were strong predictors of exposure. In exploratory analyses, the sum of the di-2-ethylhexyl phthalate metabolites (∑DEHP) and Mono-isobutyl phthalate (MiBP) were significantly associated with altered concentrations of urinary reproductive hormone metabolites. Remote, subsistence populations, like the Tsimane', offer a unique window into the health effects of endocrine active compounds because: (1) exposures are low and likely to be first generation; (2) a natural fertility lifestyle allows for exploration of reproductive effects; and (3) ever-increasing globalization will result in increasing exposure in the next decade.