Environmental phthalate exposure and preterm birth.
ABSTRACT: IMPORTANCE:Preterm birth is a leading cause of neonatal mortality, with a variety of contributing causes and risk factors. Environmental exposures represent a group of understudied, but potentially important, factors. Phthalate diesters are used extensively in a variety of consumer products worldwide. Consequently, exposure in pregnant women is highly prevalent. OBJECTIVE:To assess the relationship between phthalate exposure during pregnancy and preterm birth. DESIGN, SETTING, AND PARTICIPANTS:This nested case-control study was conducted at Brigham and Women's Hospital, Boston, Massachusetts. Women were recruited for a prospective observational cohort study from 2006-2008. Each provided demographic data, biological samples, and information about birth outcomes. From within this group, we selected 130 cases of preterm birth and 352 randomly assigned control participants, and we analyzed urine samples from up to 3 time points during pregnancy for levels of phthalate metabolites. EXPOSURE:Phthalate exposure during pregnancy. MAIN OUTCOMES AND MEASURES:We examined associations between average levels of phthalate exposure during pregnancy and preterm birth, defined as fewer than 37 weeks of completed gestation, as well as spontaneous preterm birth, defined as preterm preceded by spontaneous preterm labor or preterm premature rupture of the membranes (n?=?57). RESULTS:Geometric means of the di-2-ethylhexyl phthalate (DEHP) metabolites mono-(2-ethyl)-hexyl phthalate (MEHP) and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), as well as mono-n-butyl phthalate (MBP), were significantly higher in cases compared with control participants. In adjusted models, MEHP, MECPP, and? ??DEHP metabolites were associated with significantly increased odds of preterm birth. When spontaneous preterm births were examined alone, MEHP, mono-(2-ethyl-5-oxohexyl) phthalate, MECPP, ???DEHP, MBP, and mono-(3-carboxypropyl) phthalate metabolite levels were all associated with significantly elevated odds of prematurity. CONCLUSIONS AND RELEVANCE:Women exposed to phthalates during pregnancy have significantly increased odds of delivering preterm. Steps should be taken to decrease maternal exposure to phthalates during pregnancy.
Project description:Previous studies revealed that phthalate exposure could alter thyroid hormones during the last trimester of pregnancy. However, thyroid hormones are crucial for fetal development during the first trimester. We aimed to clarify the effect of phthalate exposure on thyroid hormones during early pregnancy.We recruited 97 pregnant women who were offered an amniocentesis during the early trimester from an obstetrics clinic in southern Taiwan from 2013 to 2014. After signing an informed consent form, we collected amniotic fluid and urine samples from pregnant women to analyze 11 metabolites, including mono-ethyl phthalate (MEP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethylhexyl) phthalate (MEHP), mono-butyl phthalate (MnBP), of 9 phthalates using liquid chromatography/ tandem mass spectrometry. We collected blood samples from each subject to analyze serum thyroid hormones including thyroxine (T4), free T4, and thyroid-binding globulin (TBG).Three phthalate metabolites were discovered to be >80% in the urine samples of the pregnant women: MEP (88%), MnBP (81%) and MECPP (86%). Median MnBP and MECPP levels in pregnant Taiwanese women were 21.5 and 17.6 ?g/g-creatinine, respectively, that decreased after the 2011 Taiwan DEHP scandal. Results of principal component analysis suggested two major sources (DEHP and other phthalates) of phthalates exposure in pregnant women. After adjusting for age, gestational age, TBG, urinary creatinine, and other phthalate metabolites, we found a significantly negative association between urinary MnBP levels and serum T4 (? = -5.41; p-value = 0.012; n = 97) in pregnant women using Bonferroni correction.We observed a potential change in the thyroid hormones of pregnant women during early pregnancy after DnBP exposure. Additional study is necessitated to clarify these associations.
Project description:In 2011, the Taiwan FDA disclosed illegal di(2-ethylhexyl phthalate) (DEHP) and dibutyl phthalate (DBP) use in beverage and nutrition supplements. We aim to determine phthalate exposure and other relevant factors in a sample of the general Taiwanese population in order to evaluate actual phthalate exposure levels after this disclosure of DEHP use.We selected subjects aged 7 years old and older in 2013 from the general Taiwanese population. First morning urine samples from each participant were collected to analyze 11 phthalate metabolites representing 7 parent phthalates using on-line liquid chromatography/ tandem mass spectrometry. An interview questionnaire was applied to obtain participant demographic characteristics, lifestyle, and other relevant factors.The median levels of metabolites of DEHP, including mono-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), DBP (DnBP and DiBP), including mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP), and mono-ethyl phthalate (MEP) in urine samples of 290 adults/ 97 minors (<18 years) were 7.9/ 6.1, 12.6/ 17.8, 22.0/ 25.8, 25.4/ 30.8, 18.1/ 23.6, 9.4/ 13.6 and 14.5/ 12.4 ?g/g creatinine, respectively. Women (?18 years) were exposed to significantly higher levels of MEHHP (P=0.011), MECPP (P=0.01), MnBP (P=0.001) and MEP (P<0.001) than men (?18 years), whereas no gender difference was observed in minors. We found significant higher level of MEP (creatinine-unadjusted) in subject aged between 18 to 40 years old (P<0.001), especially for women. Exposure levels of MEOHP (P<0.001), MECPP (P=0.002) and MnBP (P=0.044) in minors were significantly higher than those of adults. High frequency usage of food preservation film and bags, and personal care products are potential sources of phthalates exposure in general Taiwanese.Our findings indicated that DEHP and DBP exposure in a sample of the general Taiwanese population varied by age and gender, possibly affected by different lifestyles, and continuing bio-monitoring surveillance is warranted.
Project description:To examine prospectively associations between urinary phthalate metabolite concentrations and body size measures in children.Urinary concentrations of nine phthalate metabolites: monoethyl (MEP); mono-n-butyl (MBP); mono-(3-carboxypropyl) (MCPP); monobenzyl (MBzP); mono-isobutyl (MiBP); mono-(2-ethylhexyl) (MEHP); mono-(2-ethyl-5-oxohexyl) (MEOHP); mono-(2-ethyl-5-carboxypentyl) (MECPP); and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and the molar sum of the low molecular-weight phthalate metabolites (low MWP: MEP, MBP and MiBP) and high molecular-weight phthalate metabolites (high MWP: MECPP, MEHHP, MEOHP, MEHP and MBzP) and of four di-(2-ethylhexyl) phthalate (DEHP) metabolites (?DEHP: MEHP, MEHHP, MEOHP, MECPP) and anthropometry, including body mass index and waist circumference were measured among 387 Hispanic and Black, New York City children who were between six and eight years at cohort enrollment (2004-2007). Relationships between baseline metabolite concentrations and body size characteristics obtained one year later were examined using multivariate-adjusted geometric means for each body size characteristic by continuous and categories of phthalate metabolite concentrations. Stratified analyses by body size (age/sex specific) were conducted.No significant associations are reported among all girls or boys. Dose response relationships were seen with monoethyl phthalate and the sum of low molecular-weight phthalates and body mass index and waist circumference among overweight children; for increasing monoethyl phthalate concentration quartiles among girls, adjusted mean body mass indexes were as follows: 21.3, 21.7, 23.8, 23.5 and adjusted mean waist circumference (cm) were as follows: 73.4, 73.5, 79.2, 78.8 (p-trend<0.001 for both).In this prospective analysis we identified positive relationships between urinary concentrations of monoethyl phthalate and the sum of low molecular-weight phthalates and body size measures in overweight children. These are metabolites with concentrations above 1 ?M.
Project description:Despite increasing attention to the occupational risk of firefighters, little is known about phthalate exposure. In our study, we detected mono-isobutyl phthalate (MiBP), mono-n-buthyl phthalate (MnBP), mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MECPP), and mono(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP) in each urine sample. We detected positive association between MnBP, MiBP, mono-2-ethylhexyl phthalate (MEHP), 5OH-MEHP, 5oxo-MEHP, 5cx-MECPP, mono-isononyl phthalate (MiNP), the sum of low (?LMWP) and high molecular-weight phthalates (?HMWP). and Tiffeneau-Pinelli index (the ratio of forced expiratory volume in 1/ forced vital capacity; FEV1/FVC; p = 0.001-0.04) and the percent predicted value (%PV) of FEV1/FVC (p = 0.005-0.05) and negative association between MiNP and peak expiratory flow (PEF; r = -0.31; p = 0.084). We observed a positive association between phthalate metabolites (MnBP, 5OH-MEHP, 5oxo-MEHP, 5cx-MECPP, 2cx-MMHP, ?LMWP, and ?HMWP) and waist-to-hip ratio (WHR; p = 0.003-0.09) and body shape index (ABSI; p = 0.039-0.09) and a negative association between MnBP, ?LMWP, and hip circumference (p = 0.005-0.02). We detected association between concentrations of 5OH-MEHP, 5cx-MECPP, 5oxo-MEHP, and MnBP and consumption of food heating in plastic material in microwave (p = 0.02-0.04) and between probands who ate margarines and vegetable fat packed in plastic containers and concentration of MMP (p = 0.03). Results of multivariate regression indicated that exposure to phthalates could be linked with changing body structure, which subsequently affects values of pulmonary functions in firefighters.
Project description:Phthalate exposure was reported to be associated with diabetes mellitus (DM) and cardiovascular disease (CVD). Yet, reported associations and the potential sex differences are inconsistent. We conducted a cross-sectional study involving 2330 participants in the Fall of 2012. Urinary metabolites of 10 phthalates were measured. The status of having DM and CVD-related outcomes were self-reported. In the overall study population, the logistic regression analyses showed that the urinary levels of mono-2-ethyl-5-oxohexyphthalate (MEOHP), mono-2-ethyl-5-hydroxyhexylphthalate(MEHHP) and mono-2-ethyl-5-carboxypentylphthalate (MECPP) were positively associated with DM. Higher urinary levels of monomethyl phthalate (MMP) and mono-2-carboxymethyl-hexyl phthalate (MCMHP) were associated with increased odds of hyperlipidemia, while mono-2-ethylhexylphthalate (MEHP) was significantly inverse-associated with hyperlipidemia. We did not observe significant associations for other CVD-related outcomes with phthalate metabolites. When stratifying by sex, MEHHP, MEOHP, MECPP, MCMHP and the micromolar sums of the oxidative metabolites of DEHP (?DEHPox) were all significantly related to DM in males, but not in females. No significant sex differences were found in CVD-related outcomes, except the sporadic associations between phthalates and hyperlipidemia. These findings highlight the importance of investigating the sex-specific relationship between phthalates exposure and DM.
Project description:Mediation analysis is useful for understanding mechanisms and has been used minimally in the study of the environment and disease.We examined mediation of the association between phthalate exposure during pregnancy and preterm birth by oxidative stress.This nested case-control study of preterm birth (n = 130 cases, 352 controls) included women who delivered in Boston, Massachusestts, from 2006 through 2008. Phthalate metabolites and 8-isoprostane, an oxidative stress biomarker, were measured in urine from three visits in pregnancy. We applied four counterfactual mediation methods: method 1, utilizing exposure and mediator averages; method 2, using averages but allowing for an exposure-mediator interaction; method 3, incorporating longitudinal measurements of the exposure and mediator; and method 4, using longitudinal measurements and allowing for an exposure-mediator interaction.We observed mediation of the associations between phthalate metabolites and all preterm birth by 8-isoprostane, with the greatest estimated proportion mediated observed for spontaneous preterm births specifically. Fully utilizing repeated measures of the exposure and mediator improved precision of indirect (i.e., mediated) effect estimates, and including an exposure-mediator interaction increased the estimated proportion mediated. For example, for mono(2-ethyl-carboxy-propyl) phthalate (MECPP), a metabolite of di(2-ethylhexyl) phthalate (DEHP), the percent of the total effect mediated by 8-isoprostane increased from 47% to 60% with inclusion of an exposure-mediator interaction term, in reference to a total adjusted odds ratio of 1.67 or 1.48, respectively.This demonstrates mediation of the phthalate-preterm birth relationship by oxidative stress, and the utility of complex regression models in capturing mediated associations when repeated measures of exposure and mediator are available and an exposure-mediator interaction may exist. Citation: Ferguson KK, Chen YH, VanderWeele TJ, McElrath TF, Meeker JD, Mukherjee B. 2017. Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy. Environ Health Perspect 125:488-494;?http://dx.doi.org/10.1289/EHP282.
Project description:Di-2-ethylhexyl phthalate (DEHP) is an environmental contaminant commonly used as a plasticizer in polyvinyl chloride products. Exposure to DEHP has been linked to adverse pregnancy outcomes in humans including preterm birth, low birth-weight, and pregnancy loss. Although oxidative stress is linked to the pathology of adverse pregnancy outcomes, effects of DEHP metabolites, including the active metabolite, mono-2-ethylhexyl phthalate (MEHP), on oxidative stress responses in placental cells have not been previously evaluated. The objective of the current study is to identify MEHP-stimulated oxidative stress responses in human placental cells. We treated a human placental cell line, HTR-8/SVneo, with MEHP and then measured reactive oxygen species (ROS) generation using the dichlorofluorescein assay, oxidized thymine with mass-spectrometry, redox-sensitive gene expression with qRT-PCR, and apoptosis using a luminescence assay for caspase 3/7 activity. Treatment of HTR-8 cells with 180?M MEHP increased ROS generation, oxidative DNA damage, and caspase 3/7 activity, and resulted in differential expression of redox-sensitive genes. Notably, 90 and 180?M MEHP significantly induced mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2), an enzyme important for synthesis of prostaglandins implicated in initiation of labor. The results from the present study are the first to demonstrate that MEHP stimulates oxidative stress responses in placental cells. Furthermore, the MEHP concentrations used were within an order of magnitude of the highest concentrations measured previously in human umbilical cord or maternal serum. The findings from the current study warrant future mechanistic studies of oxidative stress, apoptosis, and prostaglandins as molecular mediators of DEHP/MEHP-associated adverse pregnancy outcomes.
Project description:Di-2-ethylhexyl terephthalate (DEHTP), a structural isomer of di-2-ethylhexyl phthalate (DEHP), is a plasticizer used in a variety of commercial applications, but data on Americans' exposure to DEHTP do not exist. We investigated the exposure to DEHTP in a convenience group of U.S. adults by analyzing urine collected anonymously in 2000 (N?=?44), 2009 (N?=?61), 2011 (N?=?81), 2013 (N?=?92), and 2016 (N?=?149) for two major DEHTP oxidative metabolites: mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and mono-2-ethyl-5-hydroxyhexyl terephthalate (MEHHTP). For comparison, we also quantified the analogous DEHP metabolites mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) and mono-2-ethyl-5-carboxypentyl phthalate (MECPP). We detected MECPTP, MEHHP, and MECPP in all samples collected in 2016 with geometric means of 13.1, 4.1, and 6.7 ng/mL, respectively; we detected MEHHTP in 91% of the samples (geometric mean?=?3.1 ng/mL). Concentrations of MECPTP correlated well with those of MEHHTP (R 2?=?0.8, p?<?0.001), but did not significantly correlate with those of MEHHP (p?>?0.05) suggesting different sources of exposure to DEHP and DEHTP. We also evaluated the fraction of the metabolites eliminated in their free (i.e., unconjugated) form. The median percent of unconjugated species was lower for the DEHP metabolites (MECPP [45.5%], MEHHP [1.9%]) compared to the DEHTP metabolites (MECPTP [98.8%], MEHHTP [21.2%]). Contrary to the downward trend from 2000 to 2016 in urinary concentrations of MEHHP and MECPP, we observed an upward trend for MEHHTP and MECPTP. These preliminary data suggest that exposure to DEHTP may be on the rise. Nevertheless, general population exposure data using MEHHTP and MECPTP as exposure biomarkers would increase our understanding of exposure to DEHTP, one of the known DEHP alternatives.
Project description:Di-(2-ethylhexyl)phthalate (DEHP) is a common endocrine disrupting compound (EDC) present in the environment as a result of industrial activity and leaching from polyvinyl products. DEHP is used as a plasticizer in medical devices and many commercial and household items. Exposure occurs through inhalation, ingestion, and skin contact. DEHP is metabolized to a primary metabolite mono-(2-ethylhexyl)phthalate (MEHP) in the body, which is further metabolized to four major secondary metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5-OH-MEHP), mono(2-ethyl-5-oxyhexyl)phthalate (5-oxo-MEHP), mono(2-ethyl-5-carboxypentyl)phthalate (5-cx-MEPP) and mono[2-(carboxymethyl)hexyl]phthalate (2-cx-MMHP). DEHP and its metabolites are associated with developmental abnormalities and reproductive dysfunction within the human population. Progesterone receptor (PR) signaling is involved in important reproductive functions and is a potential target for endocrine disrupting activities of DEHP and its metabolites. This study used in silico approaches for structural binding analyses of DEHP and its five indicated major metabolites with PR.Protein Data bank was searched to retrieve the crystal structure of human PR (Id: 1SQN). PubChem database was used to obtain the structures of DEHP and its five metabolites. Docking was performed using Glide (Schrodinger) Induced Fit Docking module.DEHP and its metabolites interacted with 19-25 residues of PR with the majority of the interacting residues overlapping (82-95 % commonality) with the native bound ligand norethindrone (NET). DEHP and each of its five metabolites formed a hydrogen bonding interaction with residue Gln-725 of PR. The binding affinity was highest for NET followed by DEHP, 5-OH-MEHP, 5-oxo-MEHP, MEHP, 5-cx-MEPP, and 2-cx-MMHP.The high binding affinity of DEHP and its five major metabolites with PR as well as a high rate of overlap between PR interacting residues among DEHP and its metabolites and the native ligand, NET, suggested their disrupting potential in normal PR signaling, resulting in adverse reproductive effects.
Project description:BACKGROUND: Few studies have shown an association between prenatal phthalate exposure and adverse effects on neurodevelopment and behavior in young children. OBJECTIVES: We aimed to assess the relationship between prenatal exposure to phthalate esters and behavior syndromes in children at 8 years of age. METHODS: A total of 122 mother-child pairs from the general population in central Taiwan were studied from 2000 to 2009. Mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), mono-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), and three di-(2-ethylhexyl) phthalate (DEHP) metabolites-mono-2-ethylhexyl, mono-2-ethyl-5-hydroxyhexyl, and mono-2-ethyl-5-oxohexyl phthalates (MEHP, MEHHP, and MEOHP)--were measured in maternal urine collected during the third trimester of pregnancy using liquid chromatography-electrospray ionization-tandem mass spectrometry. Behavioral syndromes of children at 8 years of age were evaluated using the Child Behavior Checklist (CBCL). Associations between log10-transformed creatinine-corrected phthalate concentrations and standardized scores of the CBCL were estimated using linear regression models or multinomial logistic regressions with adjustments for potential confounders. RESULTS: Externalizing problem scores were significantly higher in association with a 1-unit increase in log10-transformed creatinine-corrected concentrations of maternal MBP (? = 4.29; 95% CI: 0.59, 7.99), MEOHP (? = 3.74; 95% CI: 1.33, 6.15), and MEHP (? = 4.28 ; 95% CI: 0.03, 8.26) after adjusting for the child's sex, intelligence, and family income. Meanwhile, MBP and MEOHP were significantly associated with Delinquent Behavior and Aggressive Behavior scores. The same pattern was found for borderline and/or clinical ranges. CONCLUSIONS: Our findings suggest positive associations between maternal DEHP and dibutyl phthalate (DBP) exposure and externalizing domain behavior problems in 8-year-old children.