Association of Early Life Exposure to Phthalates With Obesity and Cardiometabolic Traits in Childhood: Sex Specific Associations.
ABSTRACT: Few studies have investigated longitudinal associations between early life phthalate exposure and subsequent obesity and cardiovascular risks in children with inconsistent results. We aimed to evaluate the associations between phthalate exposure during gestation and childhood with offspring obesity and cardiometabolic risk factors in 500 mother-child pairs from the Rhea pregnancy cohort in Crete, Greece. Seven phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP)] were quantified in spot urine samples collected from mothers (1st trimester) and their children at 4 years of age. We calculated the molar sum of DEHP metabolites (MEHP, MEHHP, MEOHP). We measured child weight, height, waist circumference, skinfold thicknesses, blood pressure (BP), and lipids at 4 and 6 years and leptin, adiponectin, and C-reactive protein at 4 years. We used generalized estimating equations to examine associations at each age and tested for interaction by sex. Child exposure to phthalate metabolites was associated with lower BMI z-scores in boys and higher BMI z-scores in girls. Each 10-fold increase in ?DEHP was associated with a change in waist circumference of -2.6 cm (95% CI: -4.72, -0.48) in boys vs. 2.14 cm (95% CI: -0.14, 4.43) in girls (p-sex interaction = 0.003) and a change in waist-to-height ratio of -0.01 (95% CI: -0.03, 0.01) in boys vs. 0.02 (95% CI: 0.01, 0.04) in girls (p-sex interaction = 0.006). Phthalate metabolite concentrations at age 4 were negatively associated with systolic and diastolic blood pressure. MEP was associated with lower systolic BP z-scores (adj. ? = -0.22; 95% CI: -0.36, -0.08) at 4 years. MnBP and MBzP were associated with lower diastolic BP z-scores (adj. ? = -0.13; 95%CI: -0.23, -0.04, and adj. ? = -0.11; 95% CI: -0.21, -0.01, respectively). A 10-fold increase in MiBP was associated with 4.4% higher total cholesterol levels (95% CI: 0.2, 8.7). Prenatal phthalate exposure was not consistently associated with child adiposity and cardiometabolic measures. Our findings suggest that early life phthalate exposure may affect child growth and adiposity in a sex-specific manner and depends on the timing of exposure.
Project description: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.
Project description:<h4>Background</h4>Emerging evidence suggests that phthalate exposure may be associated with behavior problems in children and that these associations may be sex specific.<h4>Methods</h4>In a follow up study of 411 inner-city minority mothers and their children, mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monethyl phthalate (MEP) and four di-2-ethylhexyl phthalate metabolites (DEHP) were quantified in maternal urine samples collected during the third trimester and in child urine samples at ages 3 and 5 years. The Conners' Parent Rating Scale-Revised: Long Form (CPRS) and Child Behavior Checklist (CBCL) were administered to the mothers to assess children's behavior problems at 7 years of age. The analysis included children with available measures of CBCL, CPRS and phthalates measured in maternal urine. We performed both Quasi-Poisson regression and a mixture analysis using Weighted Quantile Sum(WQS) regression to assess the risk for CPRS scores and for internalizing and externalizing behaviors (from the CBCL) following intra-uterine exposure to the phthalate metabolites for boys and girls separately.<h4>Results</h4>Among boys, increases in in anxious-shy behaviors were associated with prenatal exposure to MBzP (Mean Ratio [MR] = 1.20, 95%CI 1.05-1.36) and MiBP (Mean Ratio (MR) = 1.22, 95%CI 1.02-1.47). Among girls, increases in perfectionism were associated with MBzP (MR = 1.15, 95%CI 1.01-1.30). In both boys and girls, increases in psychosomatic problems were associated with MiBP (MR = 1.28, 95%CI 1.02-1.60), and MnBP (MR = 1.28, 95%CI 1.02-1.59), respectively. Among girls, decreased hyperactivity was associated with two DEHP metabolites, mono(2-ethyl-5-oxohexyl) phthalate (MR = 0.83, 95%CI 0.71-0.98) and mono(2-ethyl-5-hydroxyhexyl) phthalate (MR = 0.85, 95%CI 0.72-0.99). Using weighted Quantile Sum logistic regression, no associations were found between the Weighted Quantile Sum (WQS) of phthalate metabolites and CPRS scores or externalizing and internalizing behaviors. Nonetheless, when the analysis was performed separately for DEHP and non-DEHP metabolites significant associations were found between the WQS of DEHP metabolites and social problems in boys (OR = 2.15, 95%CI 1.13-4.06, p-value = 0.02) anxious-shy problems in girls (OR = 2.19, 95%CI 1.15-4.16, p = 0.02), and emotional lability problems in all children (OR = 0.61, 95%CI 0.38-0.97, p = 0.04). MEHP and MEOHP were the most highly weighted DEHP metabolites in WQS mixture. The analysis performed with CBCL scale corroborated these associations.<h4>Conclusion</h4>Concentration of non-DEHP metabolites was associated with anxious-shy behaviors among boys. DEHP phthalate metabolites were associated with decreased hyperactivity and impulsivity among girls on CPRS scores. These findings lend further support to the adverse associations between prenatal phthalate exposure and childhood outcomes, and clearly suggest that such associations are sex and mixture specific.
Project description:BACKGROUND:Previous 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. METHODS:In 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 (?DEHP) 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. RESULTS:The 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 ?DEHP 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. CONCLUSIONS:Higher prenatal exposure to specific phthalates was associated with lower motor function among 11- year old girls while higher postnatal exposure to ?DEHP 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.
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:<h4>Background</h4>Prenatal 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.<h4>Methods</h4>We 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 log<sub>e</sub> 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).<h4>Results</h4>CGA was associated with 4 out of 6 urinary phthalates. CGA was 2.0 log<sub>e</sub> units lower at the 3<sup>rd</sup> vs. 1<sup>st</sup> quartile of mono-n-butyl phthalate (MnBP) (95% confidence interval (CI): -3.5, -0.5) in male placentas, but 0.6 log<sub>e</sub> 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 log<sub>e</sub> 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.<h4>Conclusions</h4>Prenatal 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.
Project description:INTRODUCTION:Studies on the associations between phthalate exposures and respiratory outcomes are limited. We investigated the association of phthalates exposure with pulmonary function and airway inflammation in asthmatic children. METHODS:Fifty-six children with asthma living in Seoul Metropolitan Area, Korea aged 6-16 years were enrolled. Their pulmonary function including forced expiratory volume in 1 sec (FEV1) and peak expiratory flow rate (PEFR) were measured, and the fractional exhaled nitric oxide (FeNO) as a marker of airway inflammation was examined repeatedly up to four times during the study period. Urinary levels of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), metabolites for di-(2-ethylhexyl) phthalate (DEHP), and mono-n-butyl phthalate (MnBP), a metabolite of di-n-butyl phthalate (DnBP), were also measured on the same days. The effects of phthalate metabolites on the respiratory symptoms were analyzed using linear mixed effect models with adjustment for potential cofounders. RESULTS:An increase in phthalate metabolites was associated with a decrease in pulmonary function and an increase in FeNO in asthmatic children. As one natural log-unit (ln-unit) levels of urinary MEHHP and MEOHP increased, FeNO levels on the same day increased by 19.47 ppb [95% confidence interval (CI): 9.28, 29.67] and 17.93 ppb (95% CI: 5.86, 30.01), respectively. An increases in the urinary level of MEHHP, MEOHP, and MnBP by one ln-unit was associated with a decrease in PEFR on the next day by 12.17 L/min (95% CI: 2.59, 21.74), 10.80 L/min (95% CI: 0.29, 21.32), and 13.65 L/min (95% CI: 5.07, 22.24), respectively. CONCLUSION:Phthalates, especially DEHP, may worsen pulmonary function and airway inflammation in asthmatic children. To control asthma symptoms, exposure to phthalates needs to be avoided.
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: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.
Project description:Studies reported adverse behavioral development including internalizing and externalizing problems in association with prenatal exposure to bisphenol A (BPA) and phthalates; however, findings were not sufficient due to using different assessment tools and child ages among studies. This study aimed to examine associations between maternal serum levels of BPA and phthalate metabolites and behavioral problems at preschool age.The Strengths and Difficulties Questionnaire (SDQ) was used to assess behavioral problems at 5 years of age. BPA and phthalate metabolite levels in the first trimester maternal serum was determined by LC-MS/MS for 458 children. Variables used for adjustment were parental ages, maternal cotinine levels, family income during pregnancy, child sex, birth order, and age at SDQ completed.The median concentrations of BPA, MnBP, MiBP, MEHP, and MECPP, primary and secondary metabolites of phthalates, were 0.062, 26.0, 7.0, 1.40, and 0.20 ng/ml, respectively. MECPP level was associated with increase conduct problem risk (OR?=?2.78, 95% CI 1.36-5.68) overall and the association remained after child sex stratification, and odds ratios were increased with wider confidence interval (OR?=?2.85, 95% CI 1.07-7.57 for boys, OR?=?4.04, 95% CI 1.31-12.5 for girls, respectively). BPA, ?DBPm (MnBP + MiBP), and ?DEHPm (MEHP+MECPP) levels were not associated with any of the child behavioral problems.Our analyses found no significant association between BPA or summation of phthalate metabolite levels and any of the behavioral problems at 5 years of age but suggested possible association between MECPP levels and increased risk of conduct problems.
Project description:Several experimental and observational studies have demonstrated the antiandrogenicity of several phthalates. However, there is limited evidence of an association between phthalate exposure in adult life and semen quality. The aim of this study was to examine phthalate exposure during adulthood in relation to semen quality in fertile US men. This multi-center cross-sectional study included 420 partners of pregnant women who attended a prenatal clinic in one of five US cities during 1999-2001. Nine phthalate metabolites [mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono (2-ethyl-5-carboxypentyl) phthalate (MECPP)], as well as mono-n-butyl phthalate (MBP) and mono-isobutyl phthalate (MiBP), mono (three carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP), and monoethyl phthalate (MEP)] were measured in urine collected at the same time as the semen sample. We regressed natural log-transformed (ln) sperm concentration, ln(total sperm count), ln(total motile sperm count), percent motile spermatozoa, and percent spermatozoa with normal morphology on each of the nine natural log-transformed metabolite concentrations and on the molar-weighted sum of DEHP metabolites in separate models. We fit unadjusted models and models that adjusted for confounders determined a priori. In unadjusted models, ln(MiBP) was significantly and positively associated with motility and ln(MBzP) significantly negatively associated with ln(total sperm count). In adjusted linear models, urinary metabolite concentrations of DEHP, DBP, DEP, and DOP were not associated with any semen parameter. We found an inverse association between ln(MBzP) concentrations and sperm motility (? = -1.47, 95% CI: -2.61, -0.33), adjusted for ln(creatinine concentration), geographic location, age, race, smoking status, stress, recent fever, time from sample collection and time to complete analysis. Several sensitivity analyses confirmed the robustness of these associations. This study and the available literature suggest that impacts of adult exposure to phthalates at environmental levels on classical sperm parameters are likely to be small.