Mono-n-butyl Phthalate Research Articles

The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: A prospective single-center study

BackgroundPhthalate exposure was reported to induce defects in ovarian function, and further influence embryo development and pregnancy outcomes. However, the data about the associations of phthalates with intermediate and pregnancy outcomes of in vitro fertilization (IVF) cycles are scarce in the Chinese population. MethodsA total of 663 women receiving IVF/intracytoplasmic sperm injection (ICSI) treatments in our center were enrolled in this analysis. They provided one urine sample on the day of oocyte retrieval. We measured urinary concentrations of eight phthalate metabolites. Generalized linear models were used to analyze the associations of urinary phthalate metabolites with ovarian response, fertilization, early embryo development, and pregnancy outcomes. ResultsAmong all the phthalate metabolites, mono-n-butyl phthalate (MBP) had the highest urinary concentration with a median level of 101.51 μg/g creatinine (Cr). MBP concentration was inversely associated with normal fertilization odds (overall P-trend < 0.01). There was a significant correlation of monoethyl phthalate (MEP) with decreased odds of normal fertilization in medium-concentration group compared to low-concentration group (overall P-trend = 0.02). No significant associations of metabolite concentrations with the odds of good-quality embryos on day 3 or blastocyst formation were found. Monomethyl phthalate (MMP) and MEP in medium-concentration group reduced 22.4% (95% CI: 0.64–0.94, overall P-trend = 0.04) and 21.9% (95% CI: 0.64–0.95, overall P-trend = 0.05) of the odds to gain good-quality blastocyst compared to low-concentration group. The eight phthalate metabolites were not correlated to clinical pregnancy rate, live birth rate, or early miscarriage rate. There was no significant association of di (2-ethylhexyl) phthalate (DEHP) metabolites observed with any clinical outcomes in the total population. After excluding male infertility, mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) in medium-concentration group turned to be associated with a higher number of retrieved oocytes (overall P-trend = 0.04), whereas mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) in medium-concentration group was associated with a lower odds of normal fertilization compared to low-concentration group (overall P-trend = 0.02). ConclusionsUrinary MBP concentration was much higher compared to other phthalate metabolites in this cohort of Chinese IVF/ICSI women, and also higher than it was reported by studies in other countries. MBP showed adverse impacts on fertilization. MMP and MEP could affect blastocyst quality, but not embryo quality on day 3. DEHP metabolites didn’t show consistent reproductive toxicities as demonstrated in previous studies.

Urinary concentrations of phthalate biomarkers in relation to uterine leiomyomata risk

PDS 62: Chemicals and metals: exposure and biomarkers, Johan Friso Foyer, Floor 1, August 28, 2019, 10:30 AM - 12:00 PM Background/Aim: Animal and epidemiologic studies suggest that phthalates have adverse reproductive effects. However, the association of phthalates with risk of uterine leiomyomata (UL), hormone-dependent neoplasms, is inconsistent. Only cross-sectional and case-control studies have been conducted to date. Methods: We conducted a prospective case-cohort study of urinary phthalate metabolites with UL incidence in the Study of the Environment, Lifestyle, and Fibroids (SELF), a cohort of premenopausal Black women aged 23-35 residing in Detroit, Michigan. Participants underwent transvaginal ultrasound examinations to identify UL at baseline and follow-up (20, 40 and 60 months). The Centers for Disease Control measured eight 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), and monoethyl phthalate (MEP) in a random sample selected at baseline and all incident UL cases through 60 months (n=764). We modeled cumulatively-averaged creatinine-adjusted metabolites (i.e., baseline, 20 and 40 month samples). We examined individual metabolites and the total molar sum of di(2-ethylhexyl) phthalate metabolites [ΣDEHP(MEHP+MEHHP+MEOHP+MECPP)]. Cox regression models used cumulatively-averaged quartiles to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI), adjusting for potential confounders. Results: We detected phthalate metabolites in the baseline urine of 91-100% of participants. Metabolites were weakly to highly correlated (Spearman correlations=0.19-0.97). We observed a protective association of MiBP and UL, with an adjusted IRR comparing highest vs. lowest quartiles of 0.71 (95% CI: 0.51-0.97), but found varying associations with other individual metabolites (IRRs ranging from 0.80 to 1.14). Adjusted IRRs (95% CIs) comparing ΣDEHP quartiles 2, 3, and 4 (highest) vs. 1 (lowest) were 0.92 (0.67-1.26), 0.62 (0.44-0.87), and 0.80 (0.58-1.10), respectively. Models using baseline concentrations produced comparable findings. Conclusions: In this prospective cohort of reproductive-aged Black women, individual and ΣDEHP molar sum phthalate metabolites were not strongly associated with UL risk.

Prenatal exposure to mixture of bisphenol A and mono(2-ethyl-5-hydroxyhexyl) phthalate increases body mass index of 6 month-age infants

TPS 632: Health effects of flame retardants and plasticizers, Johan Friso Foyer, Floor 1, August 27, 2019, 3:00 PM - 4:30 PM Background: Bisphenol A (BPA) and phthalates metabolites have endocrine-disrupting properties that may implicate weight dysregulation even at low doses of exposure. Studies have reported that individual prenatal exposure to BPA and phthalates have been associated with increased body mass index and adiposity while their knowledge gap on effect of co-exposure of BPA and phthalates exists. Thus, in this study we evaluated the exposure of mixture of BPA and phthalates and their influence on physical growth in infants. Methods: Among the participants (N=399) from:the Mothers and Children’s Environmental Health study in South Korea., we evaluated the effect of co-exposure and interaction of first, third trimester of pregnancy and at birth urinary BPA, mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MBP) on z-scores of height, weight and body mass index (BMI) at 6 months using linear regression, generalized additive model and Bayesian kernel machine regression(BKMR). Results: BPA at birth (β=0.08) and BPA in late pregnancy (β= 0.04) was significantly associated with weight at 6 months of age, while BPA at birth was associated with an increase in BMI at 6 months (β=0.15, p<0.05). Significant interaction (p<0.05) was found for BPA and MEHHP at birth affecting weight and BMI at 6 months. BKMR analysis showed significant effect of mixture of BPA and phthalate exposure (>90 percentile) at birth on weight (estimate= 0.25) and BMI (estimate=0.47) at 6 months. Also, BKMR analysis replicated the results for effect of BPA on weight and BMI at 6 months and for the interaction between BPA and MEHHP. Conclusion: Our results identified the effect of prenatal exposure to mixture of BPA, phthalates and their interaction on z-scores of weight and BMI at 6 months. Further studies are needed to explore the interaction of BPA and phthalates. Acknowledgement: This study was supported by Ministry of Environment, Korea.

The analysis of endocrine disruptors in patients with central precocious puberty

BackgroundA few studies have reported a positive association between phthalate exposure and pubertal timing, but several conflicting reports exist. The main objective of the study was to determine whether phthalate exposure was associated with central precocious puberty in girls.MethodsThis was a multicenter case-control study wherein 47 girls with central precocious puberty (CPP) and 47 controls (26 pre-pubertal girls and 21 pubertal girls) were enrolled. No obese girls were included. Five phthalate metabolites (creatinine adjusted) and bisphenol A (BPA) were measured in the first spot urine samples of these 94 girls in the early morning.ResultsThe median values of monobenzyl phthalate (MBzP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and mono-n-butyl phthalate (MnBP) were 3.1, 29.3, 18.0, 15.4, and 25.2 μg/g creatinine in the CPP group, 4.3, 53.7, 35.7, 29.1, and 66.0 μg/g creatinine in the pre-pubertal control group, and 1.7, 28.7, 21.4, 12.1, and 33.3 μg/g creatinine in the pubertal control group, respectively.The urinary concentration of the five phthalates was significantly lower in the CPP group than in the pre-pubertal control group (P < 0.001). Conversely, there was no significant difference in the urinary concentration of the five phthalates between the CPP and pubertal control groups (P values: 0.077 for MBzP, 0.733 for MECPP, 0.762 for MEHHP, 0.405 for MEOHP, and 0.981 for MnBP). In addition, the BPA level was not significantly different between the CPP and pubertal control groups (BPA median values: 0.63 μg/g creatinine, the CPP group; 1.7 μg/g creatinine, the pubertal control group; P value = 0.092).ConclusionsOur study showed that there was no significant difference in the urinary phthalate levels between the CPP and pubertal control groups. Moreover, phthalate metabolites were significantly lower in the CPP group than in the pre-pubertal control group. Further investigation about endocrine disruptors and pubertal progression is needed.

Accumulation and metabolism of di(n-butyl) phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) in mature wheat tissues and their effects on detoxification and the antioxidant system in grain

Di(2-ethylhexyl) phthalate (DEHP) and di(n-butyl) phthalate (DBP) are the major phthalic acid esters to be used during the plastic manufacturing process; they have emerged as pollutants that result in serious environmental problems. However, their impacts on wheat at the reproductive stage remain unclear. Here, we examined the distribution of DEHP and DBP and their respective metabolites mono(2-ethylhexyl) phthalate (MEHP) and mono-n-butyl phthalate (MBP) in mature wheat, along with the mechanism of detoxification and oxidative burst in wheat grains under DBP and DEHP stress conditions in a pot experiment. High-performance liquid chromatography showed that the contents of DBP and DEHP, as well as their metabolites, i.e., MBP and MEHP, presented the highest values in the grain, followed by the stem, leaf, and root. Entry of DBP and DEHP into the grain from the soil induced the production of reactive oxygen species, accompanied by the upregulated expression and activity of the antioxidant enzymes (e.g., cytochrome P4503A4 and peroxidase). The metacaspase type I gene was also upregulated in response to DBP and DEHP stress in grains, which is indicative of programmed cell death to maintain normal physiological activities and to resist cell damage. DBP and DEHP stress-damaged cells in the grains underwent programmed cell death by upregulating the expression levels of the metacaspase type I gene. These results provide a new perspective for improving wheat tolerance to DBP and DEHP through the use of genetic engineering strategies.

Environmental phthalate exposure and preterm birth in the PROTECT birth cohort

BackgroundPreterm birth is a global public health issue and rates in Puerto Rico are consistently among the highest in the USA. Exposures to environmental contaminants might be a contributing factor. MethodsIn a preliminary analysis from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort (n = 1090), we investigated the association between urinary phthalate metabolite concentrations measured at three study visits (targeted at 20, 24, and 28 weeks of gestation) individually and averaged over pregnancy with gestational age at delivery and preterm birth. We additionally assessed differences in associations by study visit and among preterm births with a spontaneous delivery. ResultsCompared to women in the general USA population, urinary concentrations of metabolites of di-n-butyl phthalate (DBP) and di-isobutyl phthalate (DiBP) were higher among pregnant women in Puerto Rico. Interquartile range (IQR) increases in pregnancy-averages of urinary metabolites of DBP and DiBP were associated with shorter duration of gestation and increased odds of preterm birth. An IQR increase in mono-n-butyl phthalate (MBP), a metabolite of DBP, was associated with 1.55 days shorter gestation (95% confidence interval [CI] = −2.68, −0.42) and an odds ratio (OR) of 1.42 (95% confidence interval [CI]: 1.07, 1.88) for preterm birth. An IQR increase in mono-isobutyl phthalate (MiBP), a metabolite of DiBP, was associated with 1.16 days shorter gestation (95% CI = −2.25, −0.08) and an OR of 1.32 (95% CI: 1.02, 1.71) for preterm birth. Associations were greatest in magnitude for urinary concentrations measured at the second study visit (median 23 weeks gestation). DiBP metabolite associations were greatest in magnitude in models of spontaneous preterm birth. No associations were detected with other phthalate metabolites, including those of di-2-ethylhexyl phthalate. ConclusionAmong pregnant women in the PROTECT cohort, DBP and DiBP metabolites were associated with increased odds of preterm birth. These exposures may be contributing to elevated rates of preterm birth observed in Puerto Rico.

Prenatal and early postnatal phthalate exposure and child neurodevelopment at age of 7 years – Polish Mother and Child Cohort

Phthalates are among the most frequently investigated environmental chemicals influencing children's health and particularly their neuropsychological development. However, the reported effects of these compounds on child behavior, cognitive and psychomotor outcomes are not fully consistent. The aim of this study is to evaluate the associations between prenatal and early postnatal phthalate exposures and child neurodevelopment at age of 7 years. A total of 134 mother-child pairs from Polish Mother and Child Cohort (REPRO_PL) constitute the basis for current analysis. Eleven phthalate metabolites were measured in urine samples collected from mothers in the 3rd trimester of pregnancy and from children at the age of 2 years. Child neuropsychological development at early school age (7 years) was assessed by both the Strengths and Difficulties Questionnaire (SDQ) filled by mothers and the Polish adaptation of the Intelligence and Development Scales (IDS) performed by psychologists. Mono-ethyl phthalate (MEP) concentration during pregnancy was significantly associated with increased risk of peer relationship problems in SDQ (OR = 2.7, p = 0.03). The results of the IDS analyses focused on child's cognitive and psychomotor development are not fully conclusive. Negative associations were evident between some phthalates in early childhood period and fluid intelligence and cognition (MEP: β = −5.2; p = 0.006; β = −4.2; p = 0.006; mono-n-butyl phthalate (MnBP): β = −4.9; p = 0.03; β = −4.0; p = 0.03; respectively), while positive associations have been found in the prenatal period (mono-2-ethyl-5-oxo-hexyl phthalate (oxo-MEHP): β = 3.6; p = 0.03 for fluid intelligence; β = 2.9; p = 0.03 for cognition). Further studies are required in order to elucidate which are the most critical periods of phthalate exposure on children's neurodevelopmental outcomes.

Di-n-butyl phthalate, butylbenzyl phthalate, and their metabolites exhibit different apoptotic potential in human peripheral blood mononuclear cells

Human peripheral blood mononuclear cells (PBMCs) are one of the main cell models used in studies concerning the exposure of humans (in vitro) to various chemical substances. Changes in PBMCs may reflect the general reaction of the organism regarding the effect of xenobiotics.The aim of this work was to evaluate the effect of di-n-butyl phthalate (DBP), butylbenzyl phthalate (BBP) and their metabolites: mono-n-butylphthalate (MBP), mono-benzylphthalate (MBzP) upon the induction of apoptosis in human peripheral blood mononuclear cells in vitro. PBMCs were incubated with the studied compounds at concentrations from 1 to 100 μg/mL for 12 h and/or 24 h.In order to clarify the mechanism of phthalates-induced programmed cell death, the changes in the calcium ions (Ca2+) level, alterations in the transmembrane mitochondrial potential (ΔѰm) and caspase-8, -9, -3 activity as well as externalization of phosphatidylserine have been determined.An increased Ca2+ level and a reduction of the ΔѰm were observed in PBMCs incubated with all of the studied compounds, and particularly with DBP and BBP. Phthalates caused an increase of caspases activity. The most pronounced increase was observed for caspase −9. The most pronounced pro-apoptotic changes were caused by DBP followed by BBP and then by their metabolites.

Prenatal exposure to phthalates and neurocognitive development in children at two years of age

BackgroundPhthalates are a family of endocrine disruptors with short elimination half-lives in the human body. To date, few epidemiological studies have examined repeated measures of maternal urinary phthalates and the combined effects of prenatal exposure to multiple phthalates on children's neurocognitive development. ObjectivesWe aimed to investigate the association between children's neurocognitive development at 2 years of age and prenatal phthalate exposure, as assessed by repeated measurements during pregnancy, and to further examine the effects of co-exposure to multiple phthalates using cumulative risk assessment. MethodWithin a prenatal cohort in Wuhan, China, we measured five high-molecular-weight (HMW) phthalates and three low-molecular-weight (LMW) phthalate metabolites' concentrations in three urine samples collected in the 1st, 2nd, and 3rd trimester of pregnancy from each mother. We assessed neurocognitive development by Bayley Scales of Infant and Toddler Development (BSID) at 2 years of age (n = 476) to obtain the children's mental development index (MDI) and psychomotor development index (PDI). ResultsHigher exposure levels to LMW phthalates compared to HMW phthalates were observed in our population. Ln-transformed averaged concentration of mono-n-butyl phthalate (MnBP), a metabolite of the LMW phthalate di-n-butyl phthalate (DnBP) during pregnancy, was associated with decreased PDI scores in all children (β = −1.90, 95% CI: −3.43, −0.37). Similarly, the averaged sum concentration of ∑dibutyl phthalate (∑DBP) was associated with decreased PDI scores in all children (β = −1.89, 95% CI: −3.63, −0.15). A negative trend of association between exposure to HMW phthalates and PDI scores was observed in girls, while a positive association was found in boys. In cumulative risk assessment analyses, we consistently observed that the hazard quotient of DnBP (the parent compound of MnBP) was inversely associated with PDI scores in all children, whereas the hazard quotient of di-2-ethylhexyl phthalate (DEHP), an HMW phthalate, was positively associated with PDI scores in boys only. ConclusionsThis study is the first to use repeated measurement of maternal urinary phthalates in all three trimesters to assess prenatal exposure in relation to children's neurodevelopment. Our study suggested a negative association between prenatal exposure to MnBP and children's psychomotor development, and potentially sex-specific associations between HMW phthalates and neurocognitive development among boys and girls. These findings warrant further confirmation.

Inverse associations of bisphenol A and phthalate metabolites with serum bilirubin levels in Korean population.

Bisphenol A (BPA) and phthalates are endocrine disruptors that can induce oxidative stress. Serum bilirubin has antioxidant properties and may serve as a biomarker of oxidative stress. The objective of this study was to explore the relationship of BPA and phthalates with serum bilirubin levels in a Korean population. Urinary concentrations of BPA and six phthalate [mono-n-butyl phthalate (MnBP), mono-iso-butyl phthalate (MiBP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5- hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono-benzyl phthalate (MBzP)] were measured in 709 participants. Serum concentrations of BPA and three phthalate metabolites [MnBP, MiBP, and mono-(2-ethylhexyl) phthalate (MEHP)] were measured in 752 participants. After excluding missing variables, associations between above chemicals and serum bilirubin levels were analyzed using multivariate linear regression with age, sex, BMI, GGT, GOT, GPT, and alcohol intake adjustment. Participants were further stratified by sex. Among the urinary chemicals, BPA and four phthalate metabolites (MnBP, MEOHP, MEHHP and MECPP) were inversely associated with serum bilirubin levels (BPA: β = -0.071, P < 0.0001; MnBP: β = -0.055, P = 0.025; MEOHP: β = -0.101, P < 0.0001; MEHHP: β = -0.106, P < 0.0001; MECPP: β = -0.052, P = 0.003). In a case of serum chemicals, only MiBP showed significantly positive association (β = 0.036, P = 0.016). After stratification by sex, the associations of urinary BPA remained both in male and female, of which urinary phthalates disappeared in female. The association of serum MiBP was disappeared after stratification. Urinary BPA and phthalate metabolites were inversely associated with serum bilirubin levels, whereas serum MiBP showed positive association with bilirubin. These results could provide clues for understanding the mechanisms of endocrine disruptor from oxidative stress to excretion from our body.

Unhealthy Levels of Phthalates and Bisphenol A in Mexican Pregnant Women with Gestational Diabetes and Its Association to Altered Expression of miRNAs Involved with Metabolic Disease.

Several studies indicate that bisphenol A (BPA) and phthalates may have a role in the development of metabolic diseases using different molecular pathways, including epigenetic regulatory mechanisms. However, it is unclear whether exposure to these chemicals modifies serum levels of miRNAs associated with gestational diabetes mellitus (GDM) risk. In the present study, we evaluated the serum levels of miRNAs associated with GDM (miR-9-5p, miR-16-5p, miR-29a-3p and miR-330-3p) and urinary levels of phthalate metabolites (mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP) and mono(2-ethyl hexyl) phthalate (MEHP)) and bisphenol A in GDM patients and women without GDM during the second trimester of gestation. We observed higher levels of miR-9-5p, miR-29a-3p and miR-330-3p in sera of patients with GDM compared to non-diabetic subjects. Phthalates were detected in 97–100% of urine samples, while BPA only in 40%. Urinary MEHP and BPA concentrations were remarkably higher in both study groups compared to previously reported data. Unadjusted MEHP levels and adjusted BPA levels were higher in non-diabetics than in GDM patients (p = 0.03, p = 0.02). We found positive correlations between adjusted urinary MBzP levels and miR-16-5p expression levels (p < 0.05), adjusted MEHP concentrations and miR-29a-3p expression levels (p < 0.05). We also found negative correlations between unadjusted and adjusted MBP concentrations and miR-29a-3p expression levels (p < 0.0001, p < 0.05), unadjusted MiBP concentrations and miR-29a-3p expression levels (p < 0.01). Urinary MEHP levels reflect a striking exposure to di(2-ethylhexyl) phthalate (DEHP) in pregnant Mexican women. This study highlights the need for a regulatory strategy in the manufacture of several items containing endocrine disruptors in order to avoid involuntary ingestion of these compounds in the Mexican population.

Exposure to Mixed Phthalates in Czech Preschool and School Children.

Knowledge of population exposure to phthalates based on the urinary metabolite levels is of the highest importance for health risk assessment. Such data are scarce in the Czech population. In the study conducted in 2016, six urinary phthalate metabolites were analysed in a total of 370 first morning urine samples of healthy children aged 5 and 9years, namely mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP), mono-benzyl phthalate (MBzP), mono-iso-butyl phthalate (MiBP), and mono-n-butyl phthalate (MnBP). The two latter mono-butyl phthalate isoforms dominated among all samples with geometric means of 63.0µg/L (MnBP) and 44.1µg/L (MiBP), followed by 5OH-MEHP (20.6µg/L), 5oxo-MEHP (12.9µg/L), MBzP (3.65µg/L), and MEHP (2.31µg/L). Daily intake (DI) of the parent phthalates was estimated using the creatinine-based model. The highest DI values were found for di-n-butyl phthalate (DnBP) (median 2.5µg/kg bw/day; 95th percentile 7.8µg/kg bw/day) and di-2-ethylhexyl phthalate (DEHP) (median 2.3µg/kg bw/day; 95th percentile 8.9µg/kg bw/day) in 5-year-old children. The tolerable daily intake (TDI) set by the European Food Safety Authority (EFSA) was exceeded in case of DnBP (in 1% of 9-year-olds and in 3% of 5-year-olds). Exposure risk was assessed based on hazard quotients calculation and cumulative approach for similar health effect. The combined exposure to four phthalates expressed by hazard index (HI) for reprotoxicity revealed exceeding of HI threshold in 14% of 5-year-olds and in 9% of 9-year-olds. These findings strongly support the need to reduce the burden of children by phthalates.

Contribution of phthalates and phthalate monoesters from drinking water to daily intakes for the general population

Although phthalates (PAEs) are ubiquitous in drinking water, and phthalate monoesters (MPAEs) have been recognized as the bioactive metabolites of PAEs, little information is available regarding the occurrence of MPAEs in drinking water and the contributions of PAEs and MPAEs to human exposure. In this study, the concentrations of PAEs and MPAEs in 146 samples of drinking water collected from 24 cities throughout China were determined. The mean concentrations of dimethyl phthalate (DMP), diethyl phthalate (DEP), diisobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP), and di-2-ethylhexyl phthalate (DEHP) were 14.31 ± 26.28, 5.905 ± 11.57, 103.8 ± 310.5, 595.9 ± 1794, and 178.2 ± 422.0 ng/L, respectively. Monomethyl phthalate (MMP), monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and mono-2-ethylhexyl phthalate (MEHP) were detected in drinking water for the first time, at mean concentrations of 12.1 ± 18.0, 2.4 ± 5.8, 11.3 ± 37.2, 36.3 ± 103, and 9.9 ± 18.0 ng/L, respectively. The geometric mean concentrations of MMP, MEP, MiBP, MnBP, and MEHP in urine samples collected from 1040 participants from 16 cities were 10.1, 19.3, 29.6, 47.3, and 3.63 μg/g creatinine, respectively. The concentrations of PAEs and MPAEs in drinking water and daily intakes (DIs) of PAEs from nine cities where drinking water and urine samples were simultaneously collected were used to estimate the contributions from drinking water. The percentages of DMP, DEP, DiBP, DnBP, and DEHP from drinking water accounted for DIs of 0.60%, 0.049%, 1.26%, 2.76%, and 0.56%, respectively. The percentages of MMP, MEP, MiBP, MnBP and MEHP via intake of drinking water accounted for urinary concentrations of 0.86%, 0.032%, 0.14%, 0.089%, and 0.045%, respectively.

SAT-229 HCG Alpha Might Supplant TSH during the Fetal Period to Promote Brain Development

It is widely agreed that adequate maternal thyroid hormone is necessary for proper brain development. The role of the fetal placenta in ensuring the production and delivery of thyroid hormone during fetal brain development is less well understood. We hypothesized that the placenta ‘hijacks’ the maternal thyroid in early pregnancy to ensure adequate thyroid hormone, and either or both endocrine systems are vulnerable to perturbation by phthalate exposure. We did a pilot study to examine this theory. 50 subjects were recruited in Memphis, TN into the CANDLE birth cohort study, and were were: 68% African-American, 32% White, 50% female babies, mean maternal age of 27.5 years, 28% nulliparous, 50% had greater than a high school education. Blood and urine samples were collected between 17-28 wks gestation. Infant cognition was measured by the Bayley’s Scales at 1 and 3 years of age, and combined into one measure. hCG-alpha, hCG-beta, hyperglycosylated hCG, intact hCG, thyroid stimulating hormone and free thyroxine were analyzed in maternal serum by immunofluorometric assays. Phthalate metabolites were measured in maternal urine by HPLC tandem mass spectrometry. Linear regression models, with quadratic terms, were used to estimate sex-specific associations, and then decomposed to evaluate direct vs. indirect effects of phthalates on infant cognition: phthalates > placental hormone > thyroid hormone > infant cognition. Consistent with previous knowledge, TSH was negatively associated with FT4 (-0.23 pmol/l per log TSH, 95% CI -0.4, -0.1) and both hormones were related to infant cognition, but without statistical significance. hCG-alpha was significantly associated with infant cognition (u-shaped), positively associated with TSH (0.38 log units TSH, 95% CI -0.1, 0.8), negatively associated with FT4 in females (-0.84 pmol/l FT4, 95% CI -1.8, 0.1). Of the phthalates, only mono-n-butyl phthalate (MnBP) was associated with lower hCG-alpha (-0.14 log units, 95% CI -0.3, 0.1), higher FT4 (1.11 pmol/l, 95% CI 0.5, 1.8) in females, and infant cognition to year 3 (-0.11 log units in females, 95% CI -0.2, 0.0). The MnBP indirect effect on cognition, through the hormones, was null. Pilot data were underpowered to generate robust findings, but provided insights: 1) hCG-alpha has a distinct correlation structure, different from the other forms of hCG, in relation to MnBP, thyroid hormone, and infant cognition; 2) these data offer support for the theory that hCG-alpha supplants TSH during this critical period of brain development. Endocrine pathways in pregnancy are related to fetal brain development and vulnerable to phthalate exposure. These types of effects can be studied by the measurement of relevant hormones. Funding was provided by The Department of Epidemiology at the University of Pittsburgh, NIEHS, Vanderbuilt University CTSA, and the Urban Child Institute.

Racial disparity in maternal phthalates exposure; Association with racial disparity in fetal growth and birth outcomes

Experimental and observational data implicate phthalates as developmental toxicants. However, few data are available to assess the maternal risks of gestational exposure by race and infant sex. To begin to address this data gap, we characterized associations between maternal urinary phthalate metabolites and birth outcomes among African American and white mothers from a southeastern U.S. population. We enrolled pregnant African American (n = 152) and white (n = 158) women with singleton live births between 18 and 22 weeks gestation. We measured phthalate metabolites (mono-n-butyl phthalate (MBP), monoisobutyl phthalate (MiBP), 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), monomethyl phthalate (MMP), and the sums of DEHP (ΣDEHP) and DBP (ΣDBP) metabolites) in up to two gestational urine specimens from mothers, and evaluated confounder-adjusted associations per natural log unit greater concentration with birth weight for gestational age z-score, small for gestational age (SGA; <10th %tile), preterm birth (PTB; <37 weeks gestation), and low birth weight (LBW; <2500 g). We also tested for interactions by maternal race and infant sex. We found that lower z-scores were associated with greater MiBP (β = −0.28; 95% CI: −0.54, −0.02) and MMP (β = −0.30; 95% CI: −0.52, −0.09) concentrations, while MEP interacted with race (p = 0.04), indicating an association among whites (β = −0.14; 95% CI: −0.28, 0.001) but not among African Americans (β = 0.05; 95% CI = −0.09, 0.19). Greater MiBP (OR = 2.82; 95% CI: 1.21, 6.56) and MEOHP (OR = 2.80; 95% CI: 1.05, 7.42) were associated with an overall higher SGA risk, greater MEHP was associated with higher SGA risk (p = 0.10) in whites (OR = 3.26 95% CI: 0.64, 16.56) but not in African Americans (OR = 0.71 95% CI: 0.07, 7.17), and the associations for MiBP (p = 0.02) and ΣDBP (p = 0.02) varied by infant sex. We detected interactions for PTB in which African Americans were at higher risk than whites for greater MiBP (p = 0.08) and MEP (p = 0.02) although lower risk for greater MEHP (p = 0.09). Greater MEP was associated with an overall higher LBW risk (OR = 1.33; 95% CI: 0.95, 1.86), and males were at higher risk than females with greater MBP (p = 0.002), MiBP (p = 0.02), MBzP (p = 0.01), MEP (p = 0.002), MMP (p = 0.09), and ΣDBP (p = 0.01) concentrations. Overall, our results suggest that gestational phthalate exposure is associated with adverse maternal birth outcomes, and that the effects vary by maternal race and infant sex.

Phthalate exposure increases subclinical atherosclerosis in young population

The link between phthalate exposure and the risk of subclinical atherosclerosis in young population remains unclear. This study investigated the association between phthalate exposure and subclinical atherosclerosis, in terms of carotid intima-media thickness (CIMT), in young population. From a nationwide mass urine screening for renal health, conducted in 1992–2000 among school children 6–18 years of age in Taiwan, we recruited 789 subjects to participate in the cardiovascular health examination in 2006–2008. Among them, 787 received measurements of 7 urinary phthalate metabolites and CIMT. Results showed both mean and maximal values of CIMT at all segments of carotid arteries significantly increased with the urinary mono-2-ethylhexyl phthalate (MEHP), ∑ di-(2-ethylhexyl) phthalate (DEHP), and mono-n-butyl phthalate (MnBP) in a dose-response relationship after adjustment for multiple linear regression models. Multivariate logistic regression analysis showed that higher quartiles of urinary concentrations of MEHP, ∑DEHP, and MnBP were associated with a higher risk of thicker CIMT. Compared to subjects with the lowest quartile (Q1) of urinary MEHP, the adjusted odds ratios (95% confidence interval) for thicker CIMT among subjects with higher urinary MEHP were 2.13 (1.18–3.84) at Q2, 4.02 (2.26–7.15) at Q3 and 7.39 (4.16–13.12) at the highest Q4. In conclusion, urinary phthalate metabolites of MEHP, ∑DEHP, and MnBP are strongly associated with CIMT in adolescents and young adults in Taiwan.

Variation in metabolism and degradation of di-n-butyl phthalate (DBP) by high- and low-DBP accumulating cultivars of rice (Oryza sativa L.) and crude enzyme extracts

Crops can take up and accumulate di-n-butyl phthalate (DBP), an extensively used plasticizer with endocrine disrupting effect, which poses potential risk to human health. Our previous study found the genotype variation in accumulation of DBP by different cultivars of rice (Oryza sativa L.). Nevertheless, the effect of DBP metabolism in vivo on the accumulation variation among different plant cultivars remains unknown. In this study, metabolism variation of DBP by low (Fengyousimiao) and high (Peizataifeng) DBP-accumulating cultivars of rice and the key enzymes involving in DBP metabolism in rice plants were investigated using in vivo exposure of rice plants and in vitro exposure of root crude enzyme extracts. Both mono-n-butyl phthalate (MBP) and phthalic acid (PA) were detected as DBP metabolites in all rice tissues (i.e., roots, stems, leaves) and crude enzyme extracts with MBP predominance. DBP metabolism occurred simultaneously when DBP uptake with the highest metabolism in roots in vivo. Degradation of DBP in root crude enzyme extracts fitted well with the first order kinetics (R2 = 0.49–0.76, P < 0.05). The activity of carboxylesterase (CXE) in root crude enzyme extracts was significantly positively correlated with DBP degradation rates. CXE played an important role in DBP metabolism of rice plants, confirming by the fact that triphenyl phosphate of CXE inhibitor could inhibit DBP metabolism of in vivo and in vitro exposure. This result was further confirmed by in vitro degradation of DBP with the commercial pure CXE. The crude enzyme solution from roots of Fengyousimiao with higher CXE activity had significantly higher DBP degradation rates than that of Peizataifeng. However, Fengyousimiao with lower tolerance to DBP stress and higher inhibition by triphenyl phosphate displayed lower DBP metabolism ability in vivo than Peizataifeng.

Binding ability of phthalate monoesters by Saccharomyces cerevisiae strains in vitro

The objective of the present study was to evaluate the capability of four food associated Saccharomyces cerevisiae strains to remove phthalate monoesters (PMEs), major metabolites produced in the gastrointestinal tract before absorption once phthalates being ingested, from aqueous solution by taking mono-n-butyl phthalate (MBP) as the representative. Consequently, all these four S. cerevisiae strains were able to remove four categories of common PMEs compounds from the aqueous solution. However, the binding capability is strain-specific; S. cerevisiae strains Y50-7 and YS102 presented higher removal capability of around 60% binding rate at the 50 mg/L of MBP. The removal capability depends on both initial MBP and yeast cell concentrations. In addition, the binding is a fast process with 15 min achieving a considerable removal level and 4 h reaching equilibrium, and strongly depends on pH (pH 3.0 is best for removal process) and temperature. The investigation for stability of yeast/MBP complexes showed that lower percentage of released MBP was detected after wash treatment using water and pH 3.0 buffer, compared with pH 7.0 buffer. Under simulated gastrointestinal conditions, the binding capability also showed strain specificity; among all S. cerevisiae strains Y50-7 showed significantly higher removal capability. Hence, our results allow us to predict that S. ceresiviae Y50-7 is a good candidate for future studies to detoxify and reduce the bioavailability of phthalates and their respective metabolites, PMEs in the human diet and animal feed.

Urinary phthalate metabolites, coronary heart disease, and atherothrombotic markers

Cross-sectional studies have described an association between exposure to phthalate esters and cardiovascular risk factors. However, the association with coronary heart disease (CHD) is still unclear. A total of 180 subjects randomly selected from 336 CHD patients, and 360 age- and sex-matched non-CHD controls were included from 2008 to 2011. Urinary metabolites of phthalate esters were measured by liquid chromatography–tandem mass spectrometry. The geometric means of urinary phthalates metabolites were significantly higher for the three Di-(2-ethylhexyl)-phthalate (DEHP) metabolites, mono‐2‐ethylhexyl phthalate (MEHP), mono‐(2‐ethyl‐5‐hydroxyhexyl) phthalate, and mono‐(2‐ethyl‐5‐oxohexyl) phthalate among CHD patients in-hospital than those of being discharged. Excluding 89 CHD patients of in-hospital and hospital discharge within 2 days, we found the urinary concentrations of MEHP, mono‐n‐butyl phthalate (MnBP), and mono-isobutyl phthalate (MiBP) of 91 CHD patients discharged ≥ 3 days were higher than those of controls. Among 451 participants, those with higher tertile levels of urinary MEHP, MnBP, and MiBP showed an increased risk for CHD compared to those with lowest tertile levels; the corresponding odds ratios (95% CI) were 2.77 (1.22–6.28), 2.90 (1.32–6.4), and 3.19 (1.41–7.21), respectively, after adjustment for confounders. Higher levels of hs-CRP, fibrinogen, and D-dimer were linked with increased levels of all DEHP metabolites in CHD patients. In conclusion, exposure to DEHP and dibutyl phthalates was positively associated with CHD and this relationship may be probably mediated via atherothrombosis.

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.